REVIEWS OF INFECTIOUS DISEASES VOL. 3 No.6.
NOVEMBER-DECEMBER 1981
1981 by The University of Chicago. All rights reserved. 0162-0886/81/0306/0023$02.00
The Role of Cell-Mediated Immunity in Bacterial Infections
Helmut Hahn and Stefan H. E. Kaufmann
I. Introduction..........................
II. Expression of Antibacterial Cell-Mediated
Immunity (CMI) by Mononuclear
Phagocytes . . . . . . . . . . . . . . . . . . . . . . . . . . .
A. Macrophage-Dependent Resistance in the
Absence of Specific Immune Responses. . ..
B. Augmentation of Macrophage Numbers by
Local Proliferation and Influx of
Monocytes from the Blood. . . . . . . . . . . . . ..
C. Granuloma Formation. . . . . . . . . . . . . . . . . ..
D. Macrophage Activation............... ...
E. The Genetic Basis of Mononuclear
Phagocyte-Dependent Resistance.........
F. Role of Polymorphonuclear Leukocytes. . ..
III. Specific T Cells as Inducers of
Antibacterial CMf..................... 1227
A. Transfer of Specific Immunity by
Lymphocytes. . . . . . . . . . . . . . . . . . . . . . . . . . . 1227
B. Evidence that Antibacterial CMI is Under
Control of the Thymus.. . . .. . . . . . . . . . . . .. 1227
1. Experiments with athymic animals. . . . .. 1227
2. Experiments with antiserum to
Thy 1 antigen. . . . . . . . . . . . . . . . . . . . . . .. 1227
IV. Lymphocyte-Macrophage Interactions
in the Effector Phase of
Antibacterial CMf..................... 1227
A. Bicellular Nature of Antibacterial CMI. . . .. 1227
B. Activation of Macrophages by
T-Cell Products. . . . . . . . . . . . . . . . . . . . . . . .. 1228
1. Experiments with cell mixtures
and supernatants. . . . . . . . . . . . . . . . . . . .. 1228
2. Lymphokines........................ 1229
C. Regulation of Lymphocyte/Macrophage
Interactions by the Major
Histocompatibility Complex (MHC). . . . . ..
1. The major histocompatibility
complex . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. MHC restriction of T-cell/macrophage
interactions. . . . . . . . . . . . . . . . . . . . . . . ..
3. MHC restriction of interactions of T cells
and virus-infected target cells. . . . . . . . . ..
4. Significance of MHC restriction. . . . . . ..
V. Role of Antigen-Presenting Cells in the
Induction of CMI. . . . . . . . . . . . . . . . . . . . .. 1233
This paper is the eighth in a series edited by Ralph van Furth
dealing with the role of the phagocyte in infection.
We thank Mrs. A. Hausler and Mrs. L. Sliwka for their ex-
cellent assistance in completing this manuscript.
Please address requests for reprints to Dr. Helmut Hahn, In-
stitut fur Medizinische Mikrobiologie, Freie Universitat Berlin,
Hindenburgdamm 27, D-IOOO Berlin 45, West Germany.
From the Institut fur Medizinische Mikrobiologie, Freie
Universitiit Berlin, Berlin, West Germany
1221 VI. T-Cell Interactions in CMf. . . . . . . . . . . . .. 1234
A. The Ly-System......................... 1234
B. Interleukins as Communication Signals
1223 Between Leukocytes. . . . . . . . . . . . . . . . . . . .. 1235
C. Association of Function, Ly Phenotype,
and MHC Restriction..... . .. . . 1235
1223 D. T-Cell Subsets in Antibacterial CMI.. . . . .. 1235
E. Studies with Cloned T-Cell Lines. . . . . . . . .. 1236
F. Suppression in Antibacterial CMI... .. .. .. 1237
1223
1224 VII. Delayed-Type Hypersensitivity
Downloaded from http://cid.oxfordjournals.org/ by guest on September 24, 2013
1224 and Antibacterial Protection:
the Problem of Anergy. . . . . . . . . . . . . . . .. 1237
1226
1226 VIII. Cytokinetics and Circulation Dynamics of
T Cells of Antibacterial CMI. . . . . . . . . . .. 1239
IX. Concluding Remarks...... .. 1240
I. Introduction
Reactions of tissues to infection by non toxigenic
bacteria may be conveniently divided into two
forms: purulent and granulomatous. Purulent in-
fections, as exemplified by pneumococcal pneu-
monia [1] are characterized by short duration,
acute course, and the accumulation of polymor-
phonuclear leukocytes at sites of bacterial implan-
tation. Opsonizing antibodies exert protective ef-
fects, and, as a rule, the disease subsides after
polymorphonuclear leukocytes and mononuclear
phagocytes have phagocytized most infecting bac-
teria and killed them within phagolysosomes. Bac-
1229 teria that cause purulent infections are categorized
as extracellular bacteria; this category includes
1230
cocci as well as the gram-negative rods found in
1230 many infections (table 1).
Bacteria that elicit granulomatous tissue re-
1231
1231 sponses include the species Mycobacterium,
Brucella, and Yersinia; and Salmonella typhi, Sal-
monella paratyphi, Listeria monocytogenes and
related organisms, Francisella tularensis, Trepo-
nema pallidum, Pseudomonas mallei and Pseudo-
monas pseudomallei (the causative agents of
glanders and melioidosis, respectively), and the
recently discovered pathogen Legionella pneumo-
phila [2-4] (table 1). These bacteria also are
phagocytized by polymorphonuclear leukocytes
and mononuclear phagocytes, and phagocytosis
of these organisms may be enhanced by specific
1221
1222 Hahn and Kaufmann

Table 1. Extracellular and facultative intracellular concluded that common carriers of DTH and pro-
bacteria. tection differing from conventional antibodies
Facultative intracellular and effective by different mechanisms must exist.
Extracellular bacteria bacteria However, although Helmholz [23] in 1909 and
Cocci Mycobacterium tuberculosis Bail [24] in 1910 had already reported transfers of
Pneumococci Mycobacterium leprae tuberculin hypersensitivity using whole blood or
Streptococci Brucella species spleen homogenate, respectively, the cellular
Staphylococci Listeria monocytogenes nature of the mediators of DTH was proven by
Neisseria species Erysipelothrix rhusiopathiae
Landsteiner and Chase [25] as late as 1942. These
Gram-negative rods
Escherichia coli Yersinia species authors succeeded in initiating adoptive transfer
Klebsiella species Francisella of contact sensitivity to picryl chloride in guinea
Enterobacter species Salmonella typhi pigs with live peritoneal exudate cells, and in 1945
Serratia marcescens Salmonella paratyphi Chase [26] transferred tuberculin hypersensitivity
Proteus species Treponema pa//idum
with similar cells.
Salmonella species (except Legionella pneumophi/a
S. typhi and S. paratyphii Applications of concepts and techniques em-
Pseudomonas species and ployed in the study of DTH and transplantation
other nonfermenters immunology [27] to the problem of immunity to
Bacteroides fragi/is facultative intracellular bacteria were instrumental
Haemophi/us inf/uenzae
in proving the cellular nature of immunity in in-
Actinomycetes
fections by facultative intracellular bacteria. The
now classic concept developed mainly by Macka-
antibodies and complement as is that of extracel- ness and co-workers in the 1960s and early 1970s
lular bacteria. Yet after phagocytosis these bac- states that in the development of immunity to fac-
teria survive within polymorphonuclear leuko- ultative intracellular bacteria two cell types coop-
cytes and, at least initially, in mononuclear erate: specific T lymphocytes and mononuclear
phagocytes as well. The terms facultative intra- phagocytes. T cells act as specific inducers and
cellular parasites [5] or facultative intracellular mononuclear phagocytes as nonspecific effector
bacteria are used to indicate this fact. cells. The task of T cells is (1) to recruit and as-
Facultative intracellular bacteria cause cyclic semble mononuclear phagocytes for the formation
systemic diseases, most of which display a chronic of granulomatous lesions and (2) to activate the
course. Delayed-type hypersensitivity (DTH) to phagocytes for enhanced bactericidal activity in
antigens of the causative organisms normally ac- these lesions. Thus, expression of immunity to
companies the infection [6]. Immunization with facultative intracellular bacteria ultimately de-
live bacteria is required to induce protection pends on the performance of properly activated
[7-11]; neither dead bacteria nor culture filtrates nonspecific effector cells within properly struc-
containing antigen suffice to induce DTH [12] or tured lesions. This form of antibacterial immunity
protection [8, 9, 13-15], unless special forms of belongs to the group of immune phenomena that
immunization are employed such as incorporation are under the control of the thymus [28] and for
of antigen into complete Freund-type adjuvants which the term "cell-mediated immunity" (CMI)
[16], injection of antigen into tuberculous lesions has been coined by Turk [29].
[17], or immune modulation by BCG (bacille Cal- Recent advances in immunologic research in-
mette-Guerinj-infection [18]. clude the discovery of genetic restriction of T-cell
Mechanisms of immunity to infections by facul- function, of T-cell subclasses, and of regulatory
tative intracellular bacteria were a mystery long circuits in which specific and nonspecific cells in-
after humoral immunity had been understood teract and, as such, determine extent, duration,
[19]. Although the occurrence of DTH made it and quality of an immune response. The role of
likely that the infected host responded to faculta- macrophages, not only as phagocytes but as
tive intracellular bacteria in an immunologically regulators of the immune response by means of in-
specific way, adoptive transfer of protection [20] teractions with T cells as well, is increasingly ap-
or DTH [21, 22] could not be achieved with spe- preciated. Finally, new techniques have been de-
cific antibody. Zinsser and Mueller [21] in 1925 veloped, among which those most promising with
Cell-Mediated Immunity in Bacteria/Infections
respect to therapeutic applications are the devel-
opment of monoclonal antibodies, the cloning of
T cells, and the production in vitro of soluble me-
diators in pure form.
This review will summarize the experimental
data that have led to the classic concept of anti-
bacterial CMI and will integrate recent develop-
ments into this classic concept. Although most of
the data cited are derived from animal experi-
ments, without doubt these studies should contrib-
ute to a better understanding of the situation for
humans. The ultimate practical goal is to be able
to manipulate the immune system at will, both in
prophylaxis and therapy of infectious diseases;
however, this goal will not be reached before we
have a clear understanding of mechanisms in in-
fectious disease immunology at the cellular and
molecular levels.
II. Expression of Antibacterial Cell-Mediated
Immunity by Mononuclear Phagocytes
Antibacterial CMI is based on a bicellular mech-
anism: specific T cells act as inducers of CMI,
whereas mononuclear phagocytes express CMI by
at least three processes. (1) Resident macrophages
limit early bacterial proliferation. (2) Under the
influence of T-dependent immune mechanisms,
mononuclear phagocytes are attracted to the site
of bacterial proliferation and form granulomatous
lesions. (3) Macrophages activated by lympho-
kines act as more potent effector cells than do
nonactivated cells.
Finally, fixed cells of the mononuclear phago-
cyte lineage have been implicated as accessory cells
in the induction of immune responses. The signifi-
cance of this function is being increasingly recog-
nized (see V).
In this section, the experimental evidence for
the expression of CMI by mononuclear phago-
cytes will be summarized. The function of specific
T cells and their products will be dealt with below
(see III, IV, VI).
A. Macrophage-Dependent Resistance in the
Absence of Specific Immune Responses
The T-cell response following infection takes time
to develop. Listeria-specific T cells are not demon-
strable in mice infected with Listeria during the
first two days after infection [30]. Thus, any resis-
1223
tance expressed before that time must be consid-
ered T-cell independent. Also, congenitally athy-
mic (nul nu) mice initially can protect themselves
against infection with Listeria and produce ac-
tivated macrophages [31-37]. In fact, one group
reported that athymic mice in the early phase of
infection killed 10 times more Listeria than did eu-
thymic mice [38]. Thymectomized, X-irradiated,
and bone marrow-reconstituted (Txbm) mice,
which lack T cells, have been reported by Camp-
bell et al. [39] as displaying a state of heightened
resistance (although not consistently). Newborg
and North [38] could distinguish an X-ray resis-
tant, preexisting state of resistance and an X-ray
sensitive mechanism, both of which were non-
specific. The X-ray sensitive mechanism was more
active during an ongoing listeria infection and was
instrumental in reducing an initial bacterial in:
oculum. Most probably this mechanism is
mediated by resident macrophages.
Nonspecific mechanisms would gain particular
importance in infections due to bacteria that have
short generation times, since such organisms reach
overwhelming numbers before T cell-mediated
immunity had time to develop. Over the long run,
however, T cell-dependent mechanisms are indis-
pensable, and animals lacking functional T cells
succumb to the infection.
B. Augmentation of Macrophage Numbers by Local
Proliferation and Influx of Monocytes from the Blood
Simultaneously with the onset of the specific im-
mune response, the number of macrophages at the
infection site increases. This increase is achieved in
two ways. (1) As shown for infections with Lis-
teria, BCG, or Brucella, resident macrophages
proliferate [40-42]. For instance, in one particular
report [43], the number of macrophages in the liv-
ers of Listeria-infected mice increased 18-fold. (2)
The bulk of mononuclear phagocytes present in
infected tissues, however, are derived from circu-
lating blood monocytes and are attracted into the
lesions [44].
The relative importance of blood-borne mono-
cytes and resident macrophages to the expression
of immunity became clear when mice that were
shielded except for their livers were irradiated to
selectively destroy the capacity of liver macro-
phages to divide. Upon infection with Listeria, the
shielded animals recruited typical macrophages
1224
into the liver and expressed immunity in that organ.
Unshielded controls, on the other hand, neither
accumulated macrophages nor developed immuni-
ty [44]. It was concluded that immigrant blood
monocytes rather than local macrophages are re-
sponsible for the expression of local immunity in
infected tissues.
C. Granuloma Formation
As accumulation of mononuclear phagocytes at
sites of infection proceeds under the influence of
immune mechanisms, the lesions become struc-
tured and granulomas form. A granuloma is
defined [45] as a "focal chronic inflammatory re-
action characterized by the accumulation and pro-
liferation of leukocytes principally of the mono-
nuclear type." Pathogenetically, two types of
granulomatous lesions can be distinguished: the
foreign body granuloma and the infectious disease
granuloma. Although both types may contribute
to a given granuloma in infectious diseases caused
by facultative intracellular bacteria, only the latter
will be dealt with here.
In the early phase, an infectious disease granu-
loma contains lymphocytes and macrophages.
Later on, such granulomas also contain epithelioid
cells, giant cells, and fibroblasts [46]. Eosinophils
are present in granulomas induced by parasites
[46], and basophils occur in lesions of cutaneous
basophil hypersensitivity [47]. Within granulomas,
cells are tightly packed, a condition that allows for
cell-to-cell interactions and for the effective con-
tainment and destruction of facultative intracellu-
lar bacteria [46] and thus, in a reduction of the
danger of further bacterial invasion and spread of
infection.
D. Macrophage Activation
The idea that macrophages become activated dur-
ing bacterial infections dates back to Metchnikoff
[48], who saw in "the perfection of the phagocytic
and digestive power of the leukocytes" the main
defense mechanism in infections. The term mac-
rophage activation was used by Mackaness [49] to
account for the increase in bactericidal capability
that macrophages acquire during infections with
facultative intracellular bacteria when the animal
develops specific DTH. In the most widely used
models, listeriosis and BCG infection of mice,
Hahn and Kaufmann
macrophage activation occurs on day 3 [9] and on
around day 9-12 after infection, respectively [50].
Activation of macrophages is not an all-or-none
effect, but rather is an increase of physiologic ac-
tivities of macrophages above the baseline values
exhibited by unstimulated cells [51]. No doubt ex-
ists that immunologic mechanisms normally are
responsible for activation of macrophages in in-
fections due to facultative intracellular bacteria.
This idea is not weakened by the fact that athymic
animals possess activated macrophages (see II A);
the mechanism by which such activation occurs is
not understood yet.
Direct evidence that macrophages from animals
infected by facultative intracellular bacteria
possess higher microbicidal activities first was ob-
tained by Lurie [52] by means of a combined in
vivo-in vitro culture system. Lurie demonstrated
that macrophages harvested from BCG-vaccinated
rabbits and infected in vitro with live tubercle ba-
cilli that were cultured in the anterior chamber of
the rabbit eye were better inhibitors of intracel-
lular bacterial multiplication than were control
macrophages from nonvaccinated donor animals.
Suter [53] developed an in vitro culture technique,
and he [54] and others [55] confirmed Lurie's find-
ing in vitro. Similar observations were made with
respect to the facultative intracellular bacteria
Brucella [14, 56, 57], F. tularensis [58], Sal-
monella [8, 59-61], and L. monocytogenes [9,
62-64].
Once established, the enhanced microbicidal ac-
tivity of activated macrophages is nonspecific and
not only can be directed against the bacterial spe-
cies that originally led to macrophage activation
but can be directed against unrelated facultative
intracellular bacteria [11, 50, 57, 63, 65-68] and
even viruses [69], parasites [70-72], fungi [73],
and tumor cells [74-77]. These observations form
the basis of tumor therapy with BCG and other
macrophage-activating bacterial vaccines, e.g.
Corynebacterium parvum or bacterial products
[78]. The extent to which nonrelated microorga-
nisms are killed by activated macrophages varies
with the organism causing the primary infection;
e.g., macrophages from animals infected with my-
cobacteria exert a higher degree of nonspecific
killing than do macrophages from Listeria-in-
fected donors [79].
In keeping with the fact that mononuclear
phagocytes are highly adaptable [80-82] and that
Cell-Mediated Immunity in Bacterial Infections
activation represents a differentiation step [51],
activated macrophages, besides having an en-
hanced bactericidal capability, display a variety of
morphologic, functional, and biochemical charac-
teristics that distinguish them from normal, rest-
ing peritoneal macrophages (for reviews see [51,
68, 78, 80-87]).
When activated macrophages, e.g., from BCG-
immune mice, are compared with normal macro-
phages, the former appear larger, tend to spread
faster on glass surfaces and have more mitochon-
dria, lysosomes, and pinocytic vacuoles. In acti-
vated cells the Golgi complex is enlarged and there
are more free ribosomes and a more elaborate en-
doplasmic reticulum than in nonactivated cells
[68].
Phagocytosis by activated macrophages is in-
creased in vitro [67] and in vivo [88]. Phagocytosis
is the essential mechanism in antibacterial defense,
and it is not surprising that this function is
markedly enhanced in activated cells. Bacteria and
other particles coated by specific antibody and
complement are taken up by phagocytes because
the latter have surface receptors: the Fe receptor
and the C3b receptor. The Fe receptor binds spe-
cifically to the Fe portion of the heavy chain of
IgG. The C3b receptor recognizes C3 after the lat-
ter is cleaved by the C3 convertase and becomes
the C3b protein. Thus, antigens complexed with
antibody of the IgG class and that also carry C3b
form complexes that bind very avidly to macro-
phages by means of multiple bonds.
In activated macrophages the number of recep-
tors for IgG [89-91] is increased. In nonactivated
macrophages the main function of C3b receptors
is to mediate the attachment of C3b-opsonized
particles; however, activated macrophages appear
to mediate the engulfment of particles as well [91].
Receptors for C4b have been shown [92] to make
their appearance in mouse macrophages activated
with C. parvum.
A number of biochemical criteria characterize
the activated state. In mouse macrophages these
include alterations in cell components, content
and activity of enzymes, and metabolic and secre-
tory activities [87]. This subject is dealt with in an-
other review of this series [93]. Biochemical
studies of this kind have, in part, been inaug-
urated by the desire to define macrophage activa-
tion in molecular terms and to bypass the technical
difficulties that hamper in vitro bactericidal as-
1225
says. These efforts have been complicated by the
observation (see [87]) that substances other than
bacteria, e.g., thioglycollate broth or endotoxin,
can induce the same type of biochemical changes
in macrophages as do intracellular bacteria. Yet
those macrophages in which the biochemical
changes were induced by such substances do not
possess the same bactericidal activity as do mac-
rophages activated during infections by facultative
intracellular bacteria.
Cohn [51] has tried to reconcile the many di-
verging observations concerning macrophage acti-
vation by suggesting that activation of macro-
phages occurs in stages and depends on the kind of
stimulus used and that different biochemical
parameters represent different stages of macro-
phage differentiation. He has devised a scheme
(figure 1) according to which nonspecific inflam-
matory events can cause the development of most
activation parameters except HzO z production
and microbicidal and tumoricidal activities. The
latter two would only be induced by lymphocyte-
derived products released during cellular immune
reactions stimulated by exposure to facultative
intracellular bacteria. Unfortunately, the bio-
chemical basis for the killing of facultative intra-
cellular bacteria by macrophages is poorly
understood, although some authors feel that
peroxide-mediated mechanisms playa crucial role
[51].
Macrophage activation is a local event and is
most marked within granulomas or elsewhere
within inflammatory lesions induced by T cell-me-
diated immune reactions [94]. Lurie [95] found
that in rabbits ingested tubercle bacilli in the cen-
ter of granulomas display the highest degree of
destruction. Histochemically, macrophages near
the center of granulomas appear to be the richest
in lysosomal enzymes, i.e., where bacteria show
the most marked signs of destruction [52, 94, 95].
Thus, any attempt to collect activated macro-
phages from sites other than those close to cellular
immune reactions will yield macrophages that are
only marginally activated.
It is clear that granuloma formation is of great-
er importance in the control of infection than is
macrophage activation. The mere presence of acti-
vated macrophages in the absence of recruitment
mechanisms is not sufficient for controlling infec-
tion. The insufficiency of activated macrophages
alone is evident from the work of Blanden [96],
1226 Hahn and Kaufmann

Nonspecific Inflammatory Event Lymphokine-Mediated Event

1. Spreading
t
2. Metabolic response 7. H 2 0 2 production
Glucose oxidation
O 2- production 8. Microbicidal and tumoricidal
HMP shunt activity
t
3. Stimulation of E IgM C3b ingestion
Blood monocyte } t
Resident macrophage 4. Proteinase secretion
t
5. Stimulated pinocytosis
t
6. Plasma membrane
Ectoenzyme modification
5 '-Nucleotidase decreased
Alk. PDE I increased
Figure 1. Stages in the activation of mononuclear phagocytes. Reprinted with permission from the Journal of Im-
munology [51]. HMP = hexose monophosphate; E IgM C3b; = erythrocytes coated with IgM antibody and C3b;
and alk. PDE I = phosphodiesterase I.

who, working with ectromelia virus in mice, acti-
vated macrophages by a generalized graft-vs.-host
reaction and suppressed T cell-dependent recruit-
ment of macrophages. The mice died of a general-
ized ectromelia infection despite the presence of
activated macrophages. Likewise, transfer of acti-
vated macrophages does not impart systemic pro-
tection but imparts only local protection, if any-
thing at all [20]. This inability again is due to the
lack of a specific focusing mechanism.
E. The Genetic Basis of Mononuclear
Phagocyte-Dependent Resistance
L. monocytogenes. Also, chemotaxis of mono-
nuclear phagocytes was reduced in nonresistant
strains. The Lr gene thus appears to regulate the
production, maturation, and/or activation of
mononuclear phagocytes. The gene determining
this form of resistance appears to be pheno-
typically expressed in the environment of the host,
since the performance of mononuclear phagocytes
from either resistant or susceptible strains de-
pended on whether the phagocytes had been trans-
ferred into resistant or into susceptible hosts [l01].
F. Role of Polymorphonuclear Leukocytes

Several authors [97-100] have observed that
genetically determined differences in what has
been termed natural resistance to listeria infection
exist among various inbred strains of mice. This
resistance apparently is controlled by a single au-
tosomal, dominant, non-H-2-linked gene called Lr
[97, 98]. The advantage conferred by Lr has been
shown experimentally [l01] to be expressed at the
macrophage level. The basis of the advantage in
resistant animals is a greater cellularity of the bone
marrow, a decrease in the generation time of
monocyte precursors, and an ability to mount
monocytosis after injection of a saline extract of
The presence of polymorphonuclear leukocytes
(PMNs) is characteristic of the acute stage of infec-
tions by facultative intracellular bacteria, be this
the initial phase before macrophages have arrived
in large numbers or the phase when granulomas li-
quify, during which PMNs may be responsible for
the softening by enzymes of the caseous center and
for cavity formation [102, 103], However the con-
tribution of PMNs to the killing of facultative in-
tracellular bacteria is minimal, although PMNs
may playa part in the early events of the inflam-
matory response. This aspect of PMN function
has not been adequately studied.
Cell-Mediated Immunity in Bacteria/Infections
III. Specific T Cells as Inducers of Antibacterial
Cell-Mediated Immunity
A. Transfer of Specific Immunity by Lymphocytes
Although the existence of some form of specific
immunity to infections due to facultative intracel-
lular bacteria was suggested by the observation
that DTH to bacterial antigen regularly develops
during infections due to L. monocytogenes [9],
Brucella abortus [63], Salmonella species [104],
and mycobacteria [105-107], attempts to transfer
immunity with use of specific antibodies have
failed consistently [9, 20, 108]. On the other hand,
specific immunity has been transferred with use of
crude cell preparations from donor animals that
were immune to tularemia [109], typhoid [110], or
tuberculosis [11]. Subsequent to the important
observation by Wesslen [112] and by Coe et al.
[113] that pure, viable lymphocytes from thoracic
ducts of immunized donors transferred DTH,
Frenkel [114] succeeded in transferring protection
to the parasite Besnoitia jellisoni and Mackaness
[115], to L. monocytogenes. Both authors
employed specifically committed, viable splenic
lymphocytes. The role of lymphocytes was sub-
stantiated further by the use of antithymocyte
globulin [116-117a] or antilymphocyte globulin
[118], which suppressed immunity to Listeria and
mycobacteria, respectively.
Among individuals adoptively immunized and
infected (i.e., challenged by the homologous anti-
gen), changes develop identical to those in actively
immunized individuals. However, the changes oc-
cur at a faster rate, e.g., tubercle formation is ac-
celerated [106].
B. Evidence that Antibacterial CMI is Under
Control of the Thymus
1. Experiments with athymic animals. In due
course evidence was obtained that antibacterial
eMI belongs to the group of immune reactions
under the control of the thymus [28]. Mice thy-
mectomized and X-irradiated as adults showed in-
creased growth of Mycobacterium lepraemurium
in tissues [119-121], and neonatally thymecto-
mized mice were unable to develop normal levels
of antituberculous immunity [122]. Likewise,
adult rats [123] and" mice [124, 125] that were
1227
thymectomized, X-irradiated, and bone marrow-
reconstituted (Txbm), which lack functional T
cells, were defective in mounting antibacterial CMI
to Listeria and mycobacteria, respectively. These
defects were measured either in terms of reduced
recruitment of mononuclear phagocytes into le-
sions [123] or as a reduction of cell proliferation in
the spleen after infection [124] or in footpads
[125]. Although athymic (nu/nu) mice possess
activated macrophages (vide supra), their ability
to develop CMI is markedly impaired, a deficiency
seen by their failure to rid their tissues of
mycobacteria [126-129], L. monocytogenes [31,
32, 130], rickettsiae [131], fungi [132-134], viruses
[135], or parasites [136-140]. In athymic animals
infections take a more chronic course characterized
by the persistence of bacteria in internal organs
and by the absence of granulomatous lesions. In
several instances the defects could be restored by
grafts of syngeneic thymus [123, 124].
2. Experiments with antiserum to Thy 1 anti-
gen. After the discovery [141, 142] that the surface
antigen Theta (Thy 1) serves as a marker for thy-
mus-dependent T cells and antisera (anti-Thy 1) to
this antigen had become available, it was shown
that lymphocytes from Listeria-immune donor
mice, which transfer protection to listeria antigens
[143-147] and confer DTH [148] are sensitive to
anti-Thy 1 antiserum and complement and thus
belong to the Thy I-positive lymphocyte class (fig-
ure 2). Likewise, lymphocytes that control macro-
phage proliferation in vivo are sensitive to antise-
rum to Thy 1 [42]. The role of T-cell subgroups
will be discussed in VI.
IV. Lymphocyte-Macrophage Interactions in the
Effector Phase of Antibacterial CMI
A. Bicellular Nature of Antibacterial CMI
That macrophages and specific lymphocytes co-
operate in the expression of antibacterial CMI was
established in experiments in which mononuclear
phagocytes were eliminated by either cyclophos-
phamide [149], X irradiation [105, 150, 151] or
dextran sulfate 500, an agent potently toxic for
mononuclear phagocytes [152]. Mice pretreated in
any of these ways were adoptively immunized by
an appropriate dose of specific lymphocytes from
immune donor animals. On subsequent infection,
1228 Hahn and Kaufmann

8 IMMUNE CELLS 8
z
1.&.1 +ATS
1.&.1
-' Figure 2. Protection against Liste-
~
Vt7
~
CllS I
IMMUNEZ ria monocytogenes by adoptively
transferred T cells from Listeria-im-
1.&.1 +A9S mune mice. Left, abrogation of the
e,

:6
1.&.1
~
t NORMAL
CELLS +NRS NO
protective capacity of Listeria-im-
mune spleen cells by treatment with
antithymocyte serum plus comple-
ment (ATS). Complement alone (nor-
Vt CELLS mal rabbit serum [NRS]) had no
-'
effect. Right, abrogation of the pro-
tective capacity of Listeria-immune
peritoneal exudate cells by treatment
with antiserum to thymocyte surface
antigen Thy 1 plus complement (A8S).
IMMUNE For further details see text. Redrawn

~ )(
with permission from the Journal of
Experimental Medicine [117a] and
Cellular Immunology [145].
3

24 48 24 48
HOURS

the pretreated mice were unable to express im-
munity despite their having received an infusion of
specific protective cells. Bone marrow-containing
monocyte precursors restored the capacity to ex-
press antibacterial eMI to X-irradiated animals
[151]. Thus, specific lymphocytes cannot protect
by themselves but need the cooperation of
mononuclear phagocytes. Likewise, in the absence
of mononuclear phagocytes, specific lymphocytes,
when added to facultative intracellular bacteria in
vitro, do not directly affect the bacteria. Similar
conditions have been reported to prevail in the
murine ectromelia system [153].
B. Activation of Macrophages by T-Cell Products
1. Experiments with cell mixtures and superna-
tants. Numerous attempts have been made to re-
produce in vitro the activation of macrophages by
T cells or their products. In general, two ap-
proaches have been used: the admixture of specific
lymphocytes with antigen and normal macro-
phages and the admixture of supernatants from
antigenically or polyclonally stimulated lympho-
cytes with normal macrophages. Activated macro-
phages then were combined with bacteria and the
number of intracellular bacteria determined after
various incubation periods.
Using a homologous system, Patterson and
Youmans [154] could activate normal mouse mac-
rophages with splenocytes from mice immunized
with attenuated Mycobacterium tuberculosis so
that the macrophages exhibited tuberculostatic ac-
tivity in vitro against virulent M. tuberculosis.
Krahenbuhl and Remington [155] used Toxo-
plasma-specific spleen cells to activate macro-
phages for activity against Listeria, thus confirm-
ing in vitro the "dogma" that the macrophage
effector function is nonspecific. In these experi-
ments, supernatants from Toxoplasma-stimulated
splenocytes led to macrophage activation. Simon
and Sheagren incubated specific lymphocytes
Cell-Mediated Immunity in Bacterial Infections
from peritoneal exudates [156] or lymph node cells
[157] from guinea pigs sensitive to tuberculin, bo-
vine y-globulin, or picrylated human serum albu-
min with homologous antigen and achieved mac-
rophage activation for enhanced killing of Listeria
and production of migration inhibition factor.
Supernatants from incubation mixtures of spe-
cific lymphocytes and homologous antigen acti-
vated macrophages for the killing of Listeria [158-
162], mycobacteria [163, 164], or Yersinia pestis
[165] as did supernatants from lymphocytes acti-
vated polyclonally by plant mitogens for the kill-
ing of Listeria [166] or Leishmania enriettii [169].
That the activation of macrophages in vitro by
T cells is a process sensitive to antithymocyte se-
rum has been shown by Krahenbuhl et al. [168],
who by treating spleen cells with antithymocyte
serum abolished their ability to activate normal
macrophages in vitro in the presence of antigen.
MaueI [169] activated macrophages parasitized
with L. enriettii with use of spleen or lymph node
cells specifically reactive to antigens of that
organism. In that study activation was abrogated
by treatment of the sensitized cells with an anti-
serum of a specificity similar to that of anti-Thy 1.
2. Lymphokines. The work discussed in the
preceding section leaves little doubt that macro-
phage activation and probably granuloma forma-
tion as well are mediated by soluble factors re-
leased by antigen-stimulated T lymphocytes. Tra-
ditionally these humoral factors have been termed
lymphokines [170]. Lymphokines have been iden-
tified on the basis of their biologic activity as mea-
sured in a particular assay, a method that has led
to the creation of operational terms such as mac-
rophage-inhibitory factor, macrophage-activating
factor, chemotactic factor, and others.
Macrophage inhibitory factor (MIF). MIF is
one of the best studied lymphokines. MIF origi-
nally was described by Bloom and Bennett [171]
and David [172]. In vitro it inhibits the migration
of macrophages from a capillary tube into a dish,
a property that forms the basis of the assay. Per-
haps the function of MIF is to prevent macro-
phages from leaving the sites of cellular immune
reactions. MIF not only is produced by antigen-
stimulated T cells but also by mitogen-activated B
and T lymphocytes [172a].
Macrophage-activating factor (MAF). In vitro
MAF causes some changes in macrophages that
1229
are like those seen in activated macrophages.
Whether or not MAF and MIF are identical has
not been determined. In an early attempt to iden-
tify and purify the soluble factor(s) responsible for
macrophage activation in vitro, Fowles et al. [159]
obtained MIF-rich fractions after Sephadex chro-
matography and found the active entity in a frac-
tion of molecular weight 25,000-50,000. Whether
this agent and MIF were identical was not deter-
mined. Recently Meltzer et al. [173] have reported
that two lymphokines can be separated chro-
matographically; one causes macrophages to have
greater tumoricidal activity and the other, to have
greater bactericidal activity. The notion that lym-
phokines actually may be involved in eMI to
facultative intracellular bacteria has been streng-
thened by the fact that production of lymphokines
by specifically reactive T cells from immune ani-
mals has been demonstrated in several cases;
thoracic duct lymphocytes from infected rats pro-
duce MIF [174] and peritoneal exudate lympho-
cytes from Listeria-immune rats produce chemo-
tactic factor [175]. The differentiation pattern and
migratory behavior of MIF-producing lympho-
cytes were identical to those of protective cells
from similarly treated animals (see above).
Finally, the appearance of MIF in the circula-
tion of mice infected with mycobacteria [176-178]
or Listeria [179] in close temporal relationship
with antigen challenge must be taken as an indica-
tion that lymphokines actually playa role in vivo.
C. Regulation of Lymphocyte/Macrophage Interactions
by the Major Histocompatibility Complex (MHC)
One of the major driving forces behind the phy-
logeny of the cellular immune system is thought to
be intracellular infections - viral and bacterial (re-
viewed in [180-185]). Therefore, perhaps it is not
surprising that immune mechanisms combating
those infections should represent "the best nature
can do" and, thus, attain model-like significance
for all of immunology.
Analysis of T cell-dependent immune mech-
anisms involved in intracellular infections must
take into consideration the peculiarities of viral
and bacterial infections. In viral infections, vir-
tually all host cells are potential targets for the
parasite, whereas in infections by facultative intra-
cellular bacteria the infecting organisms pre-
1230
dominate in cells of the mononuclear phagocyte
system. Virus-infected host cells must be lysed spe-
cifically as early as possible for viral replication to
be kept at a minimum. In intracellular bacterial in-
fections, on the other hand, immunologic destruc-
tion of phagocytic cells would be detrimental to
the host owing to dissemination of bacteria from
disrupted phagocytes. Here, accumulation and
differentiation of immunologically active cells
must be achieved without cell destruction. The
cellular immune response therefore has to ensure
that (1) lytic signals be delivered in virus infections
and (2) differentiation signals be delivered infec-
tions by intracellular bacteria. Since both the viral
antigen in infected cells and the antigens that have
been phagocytized by macrophages are expressed
on membranes, the cell membrane is the most like-
ly site of antigen encounter and recognition by
immunocompetent T cells. The discovery that
this, in fact, is so and that membrane-associated
antigens that are coded by the MHC, i.e., alloan-
tigens, represent the crucial element in the selec-
tion and restriction of cellular interactions that
generate an optimally tailored immune response,
have been the most consequential recent findings.
Since this subject has been extensively reviewed
[180-185], only a short outline of the most perti-
nent facts will be given.
1. The major histocompatibility complex. The
term major histocompatibility gene complex is
used to describe a complex of linked gene loci that
encode transplantation antigens (reviewed in
response
I
In association with Ag:
activation signals
Figure 3. Schematic diagram of the H-2 gene complex of the mouse and possible relationship between T-cell func-
tions and some of the H-2 products. Ag = antigen. (Note that the order of the H-21 subregions has been changed to
improve comprehensibility.)
Hahn and Kaufmann
[186-188]). In the mouse the MHC is located on
the 17th chromosome and is referred to as the H-2
complex; the human analogue, HLA, is found on
chromosome 6. The H-2 complex can be divided
into several loci; five of these, K, I, S, G, and D
(in order of increasing distance from the centro-
mere) have been defined (figure 3). The K, D, and
I loci are of particular importance in cellular im-
mune responses. The two loci that bound the H-2
complex, K and D (counterparts in humans: HLA-
Band HLA-A), encode the classic transplantation
antigens that are detectable by cytotoxic T cells
and alloantisera on nearly all cells. Genes of the I
locus of H-2 (counterpart in humans: HLA-D) are
involved in the genetic control of specific immune
responses to certain polypeptide antigens [189]. In
addition, it was found that the I locus also codes
for cell surface structures that are expressed on
cells of the immune system (B cells, macrophages,
and some T cells), which are crucial in the induc-
tion and regulation of immune responses [187].
Accordingly, these structures are called immune
response region-associated antigens or, in short,
Ia antigens.
2. MHC restriction of T-cell/macrophage in-
teractions. In vitro studies of the effector phase
have established that interactions between primed
T cells and macrophage-associated antigen (mea-
sured by proliferation of primed T cells) in the
guinea pig system are dependent on histocompati-
bility between antigen-pulsed macrophages and T
cells. This requirement does not encompass the
s G D
\
In association
with Ag:
lytic signals
Cell-Mediated Immunity in Bacterial Infections
whole MHC; rather, donors of T lymphocytes and
of macrophages only have to be compatible at the
H-2/ locus [190-192].
Zinkernagel [193] made use of this finding in
the study of antibacterial CMI. He could demon-
strate that transfer of immunity to Listeria by
splenic T cells in mice is H-2 restricted [193, 194],
i.e., histocompatibility of cell donors and recipi-
ents at the H-21 locus was necessary and sufficient
for antibacterial protection.
Requirement for homology at the H-21 region
has been shown for several biological functions
that depend on cooperative cell interactions. DTH
to soluble protein antigens requires the histocom-
patibility of transferred T cells and cell recipients
[195]. In humoral immune responses to thymus-
dependent antigens, helper T cells and antigen-
presenting cells must at least share the H-2/ haplo-
type [196, 197]. Finally, helper T cells of cytolytic
responses have to interact with antigen-presenting
cells that are H-21 compatible [198-200], whereas
cytolytic effector T cells and target cells must be
histocompatible at the H-2K,D loci of the MHC
for cytolytic effects to occur.
Unanue and co-workers have conducted
analyses of single steps in T-cell/macrophage in-
teractions in CMI. Co-cultivation in vitro of T
cells from Listeria-immune mice and macrophages
from normal mice pulsed with heat-killed Listeria
resulted in T-cell proliferation and the production
of a protein with mitogenic properties [201, 202]
as well as in the activation of macrophages for tu-
moricidal activity [203]. Identity of macrophages
and T cells at the H-21 locus was required; la-posi-
tive macrophages, which represent a minor frac-
tion, were essential. An initial short term, H-21
locus-restricted, contact between Listeria-specific
T cells and antigen-pulsed macrophages was
found to be the triggering event; this event was
followed by nonrestricted effects, which, most
likely, were due to mediators released by triggered
T cells [204]. Provided that production of mito-
genic protein and acquired tumoricidal capacity
reflect macrophage activation, H-21-dependent
restriction of immunity to Listeria in vivo [193,
194]-at least as far as macrophage activation is
concerned - must be placed at the level of nonspe-
cific effector molecules. A simplified scheme sum-
marizing the in vitro and in vivo data on T celli
macrophage interactions in antibacterial CMI is
presented in figure 4.
1231
3. MHC restriction of interactions of T cells
and virus-infected target cells. When Blanden et al.
[205] and Zinkernagel and Doherty [206-209] in
1974 adapted the system of Cerottini and Brunner
[210] for measuring specific cytolysis by T cells in
vitro to the study of interactions between T cells
and lymphocytic choriomeningitis virus-infected
target cells from mice, an important difference be-
tween viral and bacterial intracellular infections
came to light. For optimum cytolysis of virus-in-
fected target cells, attacker and target cells' had to
share identity at the K and/or D locus of the H-2
complex. This was found to be true also when Sen-
dai virus antigen [211] or simple chemicals [212]
were coupled exogenously to prospective target
cell membranes. Similar MHC restrictions to in-
teractions between T cell and antigen have been
described for rats [213-216], chickens [217], and
humans [218].
4. Significance of MHC restriction. Analogies
between allograft rejection and DTH to tuberculin
and chemicals prompted Mitchison [219] in 1954
to speculate that immunocompetent cells react
with bacterial antigens only when the latter are
presented on cell surfaces.
In 1959 Lawrence [220] put forth his "self-plus-
X" theory according to which immune lympho-
cytes not only would recognize antigen deter-
minants derived from intracellular parasites but
also "self structures" on the surface of infected
cells. Recognition of both self plus X would then
lead to immune responses of autoimmune type
against altered self structures.
Bloch and Nordin [221] pointed out in 1960 that
DTH occurs primarily when antigenic materials
have been phagocytized. These authors induced
DTH by injecting purified protein derivative that
was bound to viable peritoneal exudate macro-
phages from guinea pigs. Pearson and Raffel
[222] furnished evidence that application of
macrophage-digested antigen (sheep red blood
cells) will induce DTH, whereas undigested an-
tigen leads to antibody production but not to
DTH. The idea was introduced that processing of
antigen by macrophages is necessary for the induc-
tion of DTH. This ability to process antigen pro-
ductively was subsequently shown by Oppenheim
and Seeger [223] to be a unique feature of
macrophages.
The general principle that emerges from these
findings is that interactions of T cells with anti-
1232 Hahn and Kaufmann

1) 2) 3) Recognition 4)
Phagocyklsis Presentaticn of I-restricted Proliferation and
antigenplus la differentiation

(~~~. : It\C::e:::?rG~ 0
~ ~~0
0 0
iCE <iir:'~~
e ciiP"til'

5)
Contact
:E-n9ricted

~~ rnediabs released

~J
7)
Granuloma formation

.'

Figure 4. Schematic depiction of the single steps of cell-mediated immunity as analysed in the mouse system. After
infection macrophages phagocytize but do not eliminate intracellular bacteria (1). Instead, some bacteria are pro-
cessed and antigenic products presented by macrophages in association with H-2I-encoded surface structures (2). Rec-
ognition of antigen in association with H-21 products (3) results in proliferation and differentiation of specific T cells
(4) that, after a second contact with antigen in association with H-2/ products (5), now are triggered to release lym-
phokines (6). In a nonspecific way lymphokines attract and activate further macrophages to form granulomas and
eliminate intracellular bacteria (7). Only steps 5-7 have been characterized, whereas steps 2-4 have not been repro-
duced in vitro but are inferred by analogy to step 5 and to other in vitro systems.

gens (derived from either microorganisms or other
sources) that lead to CMI require that antigen be
presented on cell membranes in association with
products encoded by loci of the MHC [180-185].
Two types of interactions exist with respect to the
T cell-effector function generated: lytic interac-
tions that are associated with cell surface struc-
tures encoded by the H-2K and H-2D loci (or the
equivalent thereof) and differentiative interactions
that are associated with fa antigens. It follows that
T cells must be (1) programmed to recognize not
only foreign antigens on cell surfaces but also a
self component determined by the MHC gene
complex and (2) be selected or educated in order to
Cell-Mediated Immunity in Bacteria/Infections 1233

exert programmed effector functions. The func-
tion that the T cell ultimately will fulfill depends
on which MHC product it is able to react with.
Two major alternative hypotheses, "dual recog-
nition" and "altered self," have been developed to
explain how T cells might recognize foreign anti-
gen in association with MHC products (sum-
marized in [180-185]) (figure 5). The proposal in
the dual-recognition model is that antigen is pre-
sented at a distance from the MHC product and
that T cells possess two distinct receptor sites, one
for self (MHC product) and one for foreign anti-
gen. The altered-self hypothesis postulates that T
cells recognize a complex new antigenic determin-
ant formed from MHC-coded glycoproteins and
foreign antigen. Neither model has yet been proven
formally.
Thus, the condition for the separate handling of
viral infections and those by facultative intracellu-
lar bacteria is met. Restriction of cytolytic interac-
tions by H-2K and/or H-2D ensures the lysis of
virus-infected cells, for nearly all host cells (with
the possible exception of pancreatic B cells and of
sperm cells) express H-2K- and H-2D-coded de-
terminants and thus can focus T cells programmed
to recognize these products. On the other hand,
determinants coded by the H-2/ locus are ex-
pressed on B cells, T cells, and macrophages exclu-
sively, and hence H-2/ locus-restricted interac-
tions will only take place between these cells and
will lead to B-cell differentiation, T-cell matura-
tion, or macrophage activation, respectively. Such
interactions take place in lymphatic organs and in
inflammatory foci. Thus, in I region-restricted in-
teractions, activating signals are "focused on the
limited spectrum of cells on which they must exert
their effects" [180].
V. Role of Antigen-Presenting Cells in the
Induction of CMI
Mononuclear cells function as crucial accessory
cells, not only in secondary in vitro responses (see
[190-192, 223]) but also in the proliferation of T
lymphocytes and the induction of helper T cells
[227] in response to primary antigen [224] and
mitogen [225, 226]. Also, mixed lymphocyte reac-
tions [228, 229] and the production of T cell-
growth factor (interleukin II) [230] all require the
presence of mononuclear cells.
In defining the role of antigen-presenting cells
in the induction of immune responses, interest has
recently been concentrated on two cell types: Lan-
gerhans cells and dendritic cells (summarized in
[231, 232]). Steinman and co-workers have shown
that dendritic cells constitute a minor fraction of
splenic adherent cells, are morphologically distinct
from classical macrophages, and are nonphago-

Figure 5. Current models of anti-

gen presentation in association with
products encoded by the major histo-
compatibility complex (MHC). The
dual recognition model (upper left)
proposes that antigen is presented on
the cell surface independently of the
MHC marker. Accordingly, the T
cell has two receptors, one specific
for antigen and one for "self." In the
single recognition model (upper
right), the antigen is closely linked
with the MHC-encoded product. Ac-
cordingly, the T-cell receptor recog-
nizes antigen plus "self" in close
association. Although phenotypically
the receptor appears as a single unit,
at the molecular level this is a dual-
recognition model. The altered self-
model (bottom) proposes that MHC-
encoded products are modified by the
antigen and that the T cell recognizes
a new antigenic determinant.
1234
cytic but express fa alloantigens [233-235]. Den-
dritic cells act as potent accessory cells in antigen-
specific T-cell proliferation, stimulate syngeneic
and allogeneic mixed lymphocyte reactions, and
induce trinitrophenyl-specific cytotoxic T cells
and T cells that mediate DTH [234, 236-239]. A
possible involvement of dendritic cells in the in-
duction of cytotoxic antiviral responses and in
antibacterial CMI thus appears possible.
Langerhans cells are derived from precursors in
the bone marrow [240], bear fa alloantigens [241,
242], express Fe and C3 receptors [243], and are
potent inducers of cellular immune reactions, both
in vitro and in vivo [239, 244, 245]. Thus, Langer-
hans cells are prime candidates for cells specializ-
ing in the processing and presentation of antigen
to T cells. The prominent location of Langerhans
cells in the skin most likely ensures that most in-
vading bacteria first come into contact with them
and that bacterial antigen is presented to the T-cell
compartment in an appropriate fashion. A role of
other macrophage subpopulations in antigen pro-
cessing cannot be ruled out as yet. In one instance
[246], it has been shown that the proportion of fa-
bearing macrophages in peritoneal exudates of
mice infected with L. monocytogenes is markedly
augmented. Furthermore, among human periph-
eral macrophages a subpopulation that might
be essential for antigen-induced T-cell reactivity
has been identified with the use of monoclonal an-
tibodies [247].
VI. T-Cell Interactions in CMI
A. The Ly-Systern
The mutually exclusive functions that the T-cell
compartment must fulfill in generating lytic and
differentiation signals are not vested in a homoge-
neous pool of T cells. Mainly through the work of
Boyse and co-workers (summarized in [248, 249]),
it has become evident that the murine T-cell sys-
tem can be divided into subgroups by means of
surface markers, notably those of the Ly-system.
Ly antigens are glycoproteins that most prob-
ably are expressed on T cells exclusively (sum-
marized in [248, 250]). Of these antigens, Ly 1, Ly
2, and Ly 3 are of particular relevance to cellular
immunology, although other Ly antigens have
been described. Ly 1 has been mapped on chromo-
some 19 and Ly 2 and 3, which are linked to-
gether, on chromosome 6. Ly antigens are ex-
Hahn and Kaufmann
pressed polymorphically; therefore it is possible to
raise alloantisera that react with these differentia-
tion antigens by immunizing congenic mice. By
the use of anti-Ly sera plus complement, T-cell
subpopulations with Ly 1 or Ly 23 antigens but
not with Ly 123 antigens can be produced by
means of a negative selection process. Ly 1 T cells
express only Ly 1 antigens; Ly 23 T cells express
only Ly 2 and Ly 3; and Ly 123 T cells express all
three antigens. Ly 1, Ly 23, and Ly 123 T cells ac-
count for rv30 070, 10 070, and 50 070 of the periph-
eral T-cell pool, respectively [251]. Recent studies
have indicated that in the human T-cell system the
subpopulations are similar [252].
Although exceptions exist, it is generally ac-
cepted that different Ly-marked subsets of T cells
mediate distinct biological functions. Ly 1 T cells
are programmed to induce cell types such as B
cells (help in antibody production) and T cells
(help in the generation of Ly 23 cytolytic T cells)
to fulfill their functions [251, 253-256]. These
cells, since they have been shown to mediate DTH
to sheep red blood cells (SRBCs) and protein anti-
gen in vivo [257-259], also appear to induce
inflammatory cells such as macrophages. These
reactions represent a short-lived, Jones-Mote-type
of DTH [257, 260]. (Classical tuberculin allergy is
long-lived and possibly is regulated differently.)
Ly 1 T cells represent the predominant subclass of
proliferating cells of those involved in macro-
phage-T-cell interactions and in mixed lympho-
cyte reactions [253, 261].
Of the Ly 23 cell subset, some cells are pro-
grammed for cytotoxic responses [251, 253] and
another subgroup (suppressor T cells) is capable
of suppressing humoral and cellular immune re-
sponses [254-256, 262]. In some cases, at least,
suppressor T cells can be distinguished from cyto-
toxic T cells by the presence of determinants en-
coded by the H-2fJ sublocus [263]. A third subset,
that of Ly 123 T cells, is poorly defined. Although
it probably represents a precursor pool from
which Ly 1 and Ly 23 T cells are derived, Ly 123
cells that exert specific effector and regulator
functions have been described [264-269].
Studies, most of which have been done by Ger-
shon, Cantor, and co-workers [265, 270-273], in-
dicate that members of distinct T-cell subsets do
not exert their function in an isolated way. Rather,
they are linked to a homeostatic system consisting
of regulatory loops in which one cell type modifies
the activity of others. Thus, the qualitative out-
Cell-Mediated Immunity in Bacteria/Infections
come of an immune response is determined by in-
teractions among members of different T-cell sub-
sets, macrophages, and humoral factors (sum-
marized in [273, 274]). It must be reckoned that
visible manifestations of CMI, such as DTH reac-
tions, granuloma formation, and elimination of
bacteria, represent the final outcome of such com-
plex interactions. In these interactions, soluble
mediators (interleukins) mediate signals between
cells.
B. Interleukins as Communication Signals
Between Leukocytes
The term interleukin has been proposed for bio-
logical activities that act as signals between leuko-
cytes [275]. According to this proposal, the term
interleukin 1 (lL 1) applies to antigen-nonspecific,
lymphocyte-activating factors with molecular
weights of 12,000-18,000 that are secreted by mac-
rophages. The term interleukin 2 (lL 2) is used to
describe antigen-nonspecific, lymphocyte-activat-
ing factors with molecular weights of 30,000-
35,000 that are secreted by T cells. IL 2 has the ca-
pacity to promote and maintain long-term cultures
of T cells.
Studies done during the last few years have pro-
duced good evidence that IL 1 and IL 2 are impor-
tant transmitter substances in leukocyte communi-
cation (reviewed in [275a]). It is thought that both
interleukins function as second signals, which are
required in the process of T-cell activation in addi-
tion to antigen. Activation of Ly 1 T cells of the
helper type not only requires their interaction with
antigen presented by macrophages (signal 1) but
with macrophage-derived IL 1 (signal 2) as well.
On the other hand, in addition to recognizing anti-
gen on target cells (signal 1), Ly 23 T cells of the
cytotoxic type have to be stimulated by IL 2 se-
creted by Ly 1 helper T cells (signal 2). Further
studies will have to reveal the significance of inter-
leukins in regulating the immune response in vivo
since so far IL 1 and IL 2 have mostly been studied
in vitro.
C. Association of Function, Ly Phenotype, and
MOC Restriction
In addition to being associated with function, the
Ly phenotype also is linked with restriction pat-
terns in the recognition of MHC-associated anti-
gens. Thus, Ly 1 helper or DTH-mediating T cells
1235
recognize antigen in association with H-2/locus-
coded determinants, whereas Ly 23 cytolytic T
cells recognize antigen in association with H-2K-
and H-2D-coded products. At least in some cases,
suppressor cells can recognize antigen directly
[276], and, therefore, free antigen is able to acti-
vate suppressor T cells in the absence of MHC-
coded products [277] (figure 6).
Recent experiments indicate that suppressor T
cells can be activated by feedback mechanisms as
well [270-272]. In these studies experimental con-
ditions were chosen so that antigen did not acti-
vate suppressor T cells directly. Rather, helper T
cells were induced by B cells to support antibody
secretion by B cells. However, activation of helper
T cells was accompanied by regulatory interac-
tions among different T-cell subsets, which finally
resulted in the generation of suppressor T cells.
Suppressor T cells in turn depress the immune re-
sponse by suppressing helper T-cell activity via a
negative feedback loop. It appears, although it has
not been proven, that such suppressor circuits are
capable of controlling immune responses after the
elimination of antigen in vivo and hence are of
physiologic significance. Antibacterial immunity
might be regulated by such feedback loops (see VII).
D. T-Cell Subsets in Antibacterial CMI
Kaufmann et al. [278], using the murine listeriosis
model, have established that both antibacterial
protection and DTH are crucially dependent on the
involvement of Ly 123 T cells. These cells had
originated from Listeria-immune donors and were
active in adoptive transfer experiments. The sig-
nificance of this finding is that Ly 123 cells were
shown to be involved not only in protection but in
DTH to a bacterial antigen as well. Since a short-
lived form of DTH develops when SRBCs or solu-
ble proteins are used as antigen, a form that is me-
diated by Ly 1 T cells [257-260], the existence of at
least two types of DTH must be inferred: one me-
diated by Ly 1 T cells independently of Ly 123 T
cells and the other dependent on Ly 123 T cells.
The former type of DTH has been associated with
Jones-Mote-type reactivity [257, 278], whereas it
has not been decided yet whether the latter falls
into the group of classical, tuberculin-type reactions
or into that of Jones-Mote-type reactions. It is
necessary to establish the Ly phenotype of the T
cells involved in classic tuberculin type reactions.
These experiments [278] did not rule out the
1236 Hahn and Kaufmann

Ag- presentation Activated Tcell subset Signal Effect

Activation and Help. DTH

_ _ _~.. differentiation
Signal

Phagocytosis of intracellular bacteria

by macrop,ages

~ Dg
Free antigen by-passing macrophages
---""""'"-ti.~
Suppressor
Signal Suppression

---""""'"-ti... Lytic LysIS

signal

Virus infected nonphagocytic cell

Figure 6. Hypothetic association of antigen presentation, Ly T-cell phenotype, and T-cell function in the mouse
system. In the case of intracellular bacteria (top), antigen (Ag) is presented by macrophages in association with
H-2/-region encoded product (Ag + I), which is recognized by Ly 1 T cells (and/or their precursors). Ly 1 T cells are
now triggered to deliver activation and differentiation signals (via lymphokines?). This results in mediation of de-
layed-type hypersensitivity (DTH) or help in humoral or cellular immune responses. Free antigen is recognized by Ly
23 T cells (and/or their precursors), which are now triggered to suppress an immune response (middle). How far
H-2/J-encoded products are involved in activation of Ly 23 suppressor T cells remains to be established. At least
some Ly 23 suppressor T cells, however, have been shown to bear H-2/J-encoded surface markers. In the case of
viruses (bottom), antigen is presented by virus-infected target cells in association with H-2K, D region-encoded pro-
duct (Ag + K, D), which is recognized by Ly 23 T cells (and/or their precursors). Ly 23 T cells are now triggered to
deliver lytic signals, which results in destruction of virus-infected target cells.

participation of further subsets other than Ly 123
in antibacterial CMI. Also, the possibility that
specific Ly 123 T cells mature into Listeria-specific
effector cells of a different Ly phenotype has not
been tested. Employing the in vitro system for
measuring T-cell proliferation and macrophage
activation described in [201-203], we have found-
in accordance with observations in other sys-
tems [253, 261] -that Ly 1 T cells proliferate in
response to listerial antigens and primarily cause
the activation of macrophages for production of
thymocyte mitogenic protein [279, 279a]. This
finding is in keeping with the recently reported
observation that Ly 1 T cells produce MIF [280].
Identity of activating and attracting T cells has not
yet been shown. In fact, it appears possible that
the attracting T cells that are responsible. for
granuloma formation in vivo and the activating T
cells are not the same cells. This question awaits
further studies, especially those employing homo-
geneous clones of specific T cells.
E. Studies with Cloned T-Cell Lines
Recent developments in technology have allowed
antigen-specific T cells to be propagated in vitro
[279b]. Also, methods of T-cell cloning have
been established [279b]. Cloned T-cell lines retain
Cell-Mediated Immunity in Bacterial Infections
their antigen specificity as well as their biologic
function and thus permit the study of the bio-
logical properties of populations of homogeneous,
antigen-specific T cells. Applying these metho-
dologies, Kaufmann et al. I recently have suc-
ceeded in establishing cloned T-cell lines with
specificity for L. monocytogenes. These lines have
the characteristics of helper T cells, i.e., they bear
the Lyl +2- phenotype and are restricted by the
H-2/A-sublocus of the MHC. In vitro, cloned T
cells proliferate, induce secretion of interleukin,
and provide help to B cells in response to listerial
antigen. More importantly, in vivo a single,
cloned T-cell line is able to confer both DTH to
listerial antigen and protection against living
Listeria.
As discussed above, it has been proposed that
the selective pressure of infections with intracellu-
lar bacteria has led to the formation of a family of
H-2/A-restricted T cells that are genetically pro-
grammed to deliver signals for activation and dif-
ferentiation. The data obtained from studies using
cloned T-cell lines with specificity to L. mono-
cytogenes strongly indicate that the different
biological functions - protection and DTH - can
be mediated by one homogeneous T-cell popula-
tion that plays a central role. In such experiments,
a relatively high number of cells was required for
in vivo effects to occur. Thus it is probable that
for optimal responses to occur Listeria-specific T
cells do not act in an isolated way but rather that
under physiologic conditions regulatory interac-
tions occur with other T-cell subsets [265], at least
one of which carries the Ly 1+23+ phenotype [278].
F. Suppression in Antibacterial eMf
Few data exist on the role of suppressor mecha-
nisms in CMI to intracellular bacteria. Splenecto-
mized mice show increased protection to Listeria
[281], a change that can be reversed by the transfer
of syngeneic spleen cells [282] or humoral factors
obtained from Listeria-immune mice [283]. Al-
though it can be concluded from these findings
that splenocytes and/or their products are in-
volved in the negative regulation of CMI, the ex-
act cell types involved remain to be determined.
1 S. H. E. Kaufmann, H.. Hahn, and F. Melchers, "T-Cell
Lines with Specificity for Listeria monocytogenes: H-2 Restric-
tion and Biological Functions," manuscript in preparation.
1237
Activated macrophages are capable of inhibit-
ing immune responses in vitro (summarized in
[284]). In some cases suppression of CMI by mac-
rophages has been demonstrated in vivo as well
[285, 286]. Correlating suppressed CMI with the
appearance of inhibitory macrophages, Ellner
[287] has demonstrated that diminished prolifera-
tive responses of peripheral blood cells from pa-
tients with low resistance to pulmonary tubercu-
losis are due to the presence of adherent cells. A
similar suppressive role for adherent cells in dis-
seminated fungal infections has been suggested
[288]. In experimental models, macrophages from
mice infected with M. lepraemurium [289], BCG
[290], or large numbers of Listeria [291] also were
found to exert potent suppressor activity.
From these data it has been concluded that acti-
vation of macrophages by specific T cells will re-
sult in inhibitory activity via feedback mecha-
nisms. Inhibitory effects of macrophages are non-
specific and appear to be mediated by soluble
products; a role for prostaglandins seems firmly
established [292-295].
Suppressor T cells have been demonstrated in
infections with M. lepraemurium [289], BCG
[296] and related organisms [290], and in systemic
fungal infections [297]. However, suppressor T
cells are found more often than macrophages dur-
ing later stages of infections [289, 296]. The ap-
pearance of suppressor T cells in the immune
response to BCG was found to be preceded by a
phase of late blast transformation [296]. This
finding may indicate that in CMI suppressor T
cells are induced by feedback mechanisms rather
than by direct antigen activation and thus may
point to the possible role of suppressor T cells in
the "turning off' of the immune response after the
infection has subsided. In general, suppression in
antibacterial CMI has been a poorly studied phe-
nomenon, although this field should have great
practical importance (see VII).
VII. Delayed-Type Hypersensitivity and
Antibacterial Protection: the Problem
of Anergy
Whether a causal link exists between DTH in bac-
terial infections and protection has been a contro-
versial question ever since the description of
"Koch's phenomenon" [298]. Absence of DTH re-
actions in patients infected with intracellular bac-
1238
teria is a phenomenon termed anergy (for reviews
see [299-301]). In clinical medicine, anergy in pa-
tients with miliary tuberculosis, lepromatous lep-
rosy, disseminated cutaneous leishmaniasis, or
fungal infection is considered ominous, whereas
the return of DTH is interpreted as a favorable
sign ([see 302]). A link between DTH and protec-
tion is suggested by the close temporal relationship
between the two phenomena [105, 303] and by the
facts that both DTH and antibacterial protection
can be transferred by specific lymphocytes [112,
117a, 143-145, 147, 148] and that expression
of both DTH and protection depend on bone
marrow-derived [151, 304] mononuclear phago-
cytes [305, 306]. It has been shown recently that
Listeria are killed nonspecifically in skin lesions of
DTH in BCG-sensitized mice [307, 308]. The
conclusion has been drawn that what happens lo-
cally in lesions of DTH reflects events in infected
tissues. One important aspect of these works is that
DTH measured by footpad swelling need not be
visibly expressed but that accumulation of few
mononuclear phagocytes suffices for coping with
the bacterial load.
Reports summarizing evidence to the contrary
are equally numerous. Dissociation of DTH to tu-
berculin and immunity to M. tuberculosis has
been reported. Animals can be desensitized to tu-
berculin without losing resistance to M. tubercu-
losis or can be rendered hypersensitive without a
corresponding increase in resistance [309-314].
Certain fractions of the tubercle bacillus give a
measurable degree of resistance without produc-
ing cutaneous sensitivity [315]. After vaccination
with BCG, a certain percentage of vaccinees are
insufficiently protected [316]. Moreover, the degree
of protection against tuberculosis could not be
correlated with the rate of conversion to tubercu-
lin positivity after vaccination [317], and protec-
tive immunity has been demonstrated in the
absence of any measurable T-cell activity [318].
In a number of instances, tests showing an in-
crease in lymphocyte transformation were asso-
ciated with positive skin tests rather than with pro-
tection, e.g., in human leprosy it was noted [319]
that lymphocyte transformation ran in closer
parallel with the development of hypersensitivity
than with the development of host resistance to
the organism. DTH as it is assessed by skin testing
actually may be depressed when an intense cell-
mediated immune reaction to the same antigen is
Hahn and Kaufmann
at its peak [320]. Turk [321] points out that in
leprosy host resistance is better correlated with the
nodular granulomatous Mitsuda skin reaction
than with the classical lepromin reaction both in
patients and in experimental animals. Therefore
results of in vitro studies of macrophage activa-
tion and T-cell transformation must be interpreted
with caution with respect to mechanisms of pro-
tection in vivo. The possibility that granuloma
formation and macrophage activation are differ-
ent T-cell functions must be kept in mind.
When one tries to reconcile these observations,
heterogeneity of bacterial antigens first comes to
mind. Youmans and Youmans [309] have pointed
out that, whereas DTH and protection may de-
pend on similar mechanisms, different antigens lo-
cated on the same bacterium may be responsible
for each of these functions. Second, trapping of T
cells could result in a diminished number of T cells
in the periphery and, hence, in negative DTH re-
sponses and the depression of in vitro responses of
peripheral blood leukocytes. Indeed, in several in-
stances it has been shown that antigen deposition
in the spleen results in lymphocyte trapping, which
is enhanced and more prolonged when high doses
of antigen are used [299, 322-328]. Trapping has
been found in granulomas and/or inflammatory
foci as well as in the spleen and/or draining lymph
nodes [299, 322, 326, 327]. Perturbation of lym-
phocyte traffic during the state of anergy has been
noted in murine infections with M. lepraemurium,
[329-331] despite the fact that protection was
found to be normal at various sites.
In DTH of mice to heterologous erythrocytes,
during the suppressed state effector T cells are
present in the spleen despite the lack of peripheral
DTH responses [327]. Furthermore, T-cell func-
tions in the periphery might be affected negatively
by humoral factors such as antibodies and/or an-
tigen-antibody complexes [332]. In fact, some
anergic patients have increased levels of specific
antibodies [300]. Perhaps some forms of anergy
are due to complex regulatory mechanisms that re-
suit in the focusing of T cells in lymphoid organs
at the expense of peripheral sites and are not due
to a general suppression of CMI [328, 331, 333].
Third, different T-cell subsets may be involved
in protection and DTH. Among themselves DTH
reactions are heterogeneous. For instance, Jones-
Mote-type reactions are mediated by Ly 1 T cells
and are under the regulatory control of suppressor
Cell-Mediated Immunity in Bacteria/Injections
T cells [327], whereas DTH reactions that have
been induced under BCG modulation appear
much less affected by suppressor mechanisms
[334]. Even tuberculin reactions are heterogeneous
[335]. In the reviewer's opinion, it appears appro-
priate at this time to assume that certain forms of
DTH may be mediated by the same mechanisms as
is protection, whereas other forms may not be.
Possible differences in the susceptibility of differ-
ent mechanisms to suppression may in part offer
an explanation for the discrepancies between DTH
and protection in anergy. Certainly, precise def-
initions of the underlying pathologic mechanisms
and T-cell subsets involved are required. Again,
work with homogeneous T-cell clones most likely
will provide the final answer.
VIII. Cytokinetics and Circulation Dynamics of
T Cells of Antibacterial CMI
After antigenic challenge, specific effector T cells
of CMI are produced in stimulated lymphatic tis-
sues, i.e., spleen (iv infection) or draining lymph
nodes (sc infection). Organ weight, cellularity, and
cell proliferation are all increased [336]. Cell pro-
liferation, as measured by DNA synthesis, is most
marked in thymus-dependent areas of lymph
nodes or spleen [337], respectively, and involves T
and B cells [146]. Proliferation is related to the
number of injected viable bacteria [338], their viru-
lence [337], and the species of bacteria used for in-
jection [41, 339]. For instance, peak proliferation
in mice or rats with listeriosis, an acute infection,
occurs on day 6 postinfection [146], whereas in
spleens of mice infected with the slowly growing
virulent organism M. tuberculosis, proliferation
reaches its peak on day 12 [340]. Specific T cells of
CMI active in adoptive transfer of immunity ap-
pear and disappear in infected lymphatic organs in
parallel with the proliferative response. For in-
stance, in the spleen of Listeria-infected mice,
such T cells are demonstrable two to four days
postinfection and reach peak numbers on day 6
[146]. Subsequently, their numbers decline and
reach low levels by the 10th day postinfection [30,
50, 336]. Similar findings have been reported for
other intracellular bacterial infections and for a
variety of acute viral infections (for reviews see
[341, 342]).
The newly formed" cells leave their production
site and appear in blood or lymph. Cells active at
1239
conferring adoptive immunity could be recovered
in the thoracic duct of rats infected sc with Listeria
within three days of the infection [342]. Depend-
ing on the infection, two types of T cells, both able
to adoptively transfer protection, could be
distinguished in thoracic duct lymph. In the
acute infection listeriosis, the biologically active
cells are newly formed lymphoblasts and thus are
sensitive to the mitotic poison vinblastine [342].
Likewise, in mice, splenic T cells of immunity to
Listeria are sensitive to X irradiation and
therefore must be recently formed cells [151].
In BCG-infected rats, most of the BCG-specific T
cells released into the thoracic duct lymph during
the first week of infection belonged to the class of
lymphoblasts sensitive to vinblastine. Later on,
small lymphocytes that were vinblastine resistant
were added to the lymph in increasing numbers.
Their resistance was due to the fact that DNA syn-
thesis proceeds much more slowly in these cells.
Specific small lymphocytes also were able to pro-
tect syngeneic recipients against a challenge infec-
tion [339].
Specific T lymphoblasts formed during infec-
tion with Listeria have a short life span in the cir-
culation, whereas specific small T lymphocytes
from donors infected with mycobacteria remain in
circulation for longer periods - at least several
weeks [343]. Accordingly immunity conferred by
Listeria-specific T lymphoblasts is short-lived,
whereas small T lymphocytes from BCG-infected
rats confer long-lasting immunity [339]. More-
over, T lymphoblasts do not circulate from blood
to lymph, whereas specific small T cells do [338].
Thus, according to the type of infection (acute vs.
chronic), specific T cells are generated, some con-
ferring short-lived and others, long-lasting
immunity.
An important feature of specific effector T lym-
phoblasts of CMI is their propensity to enter in-
flammatory exudates nonspecifically [344-347].
This property is shared by T cells that mediate a
variety of T cell-dependent phenomena; in fact,
the original transfer experiment by Landsteiner
and Chase [25] employed peritoneal exudate cells.
The exudate-seeking property is not determined by
antigen specificity since Listeria-specific lym-
phoblasts can easily be attracted into peritoneal
exudates induced by caseinate, and caseinate-
induced exudates represent an excellent source of
T cells of any specificity [257, 344-347]. It is note-
1240
worthy that only lymphoblasts can enter inflam-
matory foci. Once within the exudate, these cells
mature into small specific T cells, which still con-
fer protection but no longer enter inflammatory
exudates [337, 347]. On the other hand, small spe-
cific T cells that are formed in later stages of anti-
mycobacterial immunity can leave the circulation
and enter foci of chronic, but not acute, inflam-
mations [348]. Possibly this difference is induced
by changes in the vascular structure near such foci
(for a discussion of this point see [338]).
From a teleologic standpoint, the described mi-
gration patterns of specific T cells ensure that spe-
cifically reactive T cells reach any sites of bacterial
invasion associated with an inflammatory re-
sponse. If these T cells do not encounter the ho-
mologous antigen, they are wasted. If, on the
other hand, bacterial antigens are recognized by
corresponding T cells, amplification mechanisms
that lead to accumulation and activation of mono-
nuclear phagocytes are set into motion, and the
elimination or containment of the pathogens
follows.
The migration as well as the protective capacity
of specific effector T cells of antibacterial CMI
appear to depend, at least in part, on the reduc-
tion-oxidation state of terminal carbohydrate resi-
dues of the sialic acid molecules of the membrane
[349]. Also, lymphocytotropic viruses affect
migration of specific effector cells of antibacterial
eMI [350]. Whether this is due to a lethal effect of
viruses on T cells or to alterations in cell surface
sialic acids induced by viral neuraminidase has not
been established by the work cited.
IX. Concluding Remarks
The significance of T cell/macrophage interac-
tions to the defense against intracellular bacteria is
now fully established. Major advances in our
knowledge of details in these interactions have
come from the discovery that (1) products en-
coded by the MHC regulate the cellular immune
response and (2) that different subpopulations of
T cells and mononuclear cells are interconnected
to form regulatory circuits, which determine the
quality, extent, and duration of an immune re-
sponse. Conventional immunologic methods will
no longer be adequate for the further analysis of
such complex interactions. Recent technical ad-
vances must be employed in the solution of prob-
Hahn and Kaufmann
lems of antiinfectious CMI, such as monoclonal
antibodies and homogeneous, functional T-cell
clones. Ultimately, phenomena such as antibacte-
rial protection, DTH, and anergy will be explain-
able as the result of interactions of defined mem-
bers of the immune system. New aspects and pos-
sibilities undoubtedly will emerge from this
knowledge and will allow rational approaches to
the prevention of and therapy for intracellular in-
fections with the use of adjuvants, drugs, and vac-
cination procedures.
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