20    LECTURE 2   The Innate Immune System
be dispatched to sites of infection. This whole business is
like a mail system in which there are trillions of packages
(immune system cells) that must be delivered to the
correct destinations. This delivery problem is solved by
using the same basic strategy that works so well for neu-
trophils. The key feature of the immune system’s “postal
service” is that the Velcro-like molecules which cause the
cells to roll and stop are different from cell type to cell
type and destination to destination. As a result, these cel-
lular adhesion molecules actually serve as “zip codes” to
insure that cells are delivered to the appropriate locations.
Indeed, the selectins and their ligands are really families
of molecules, and only certain members of the selectin
family will pair up with certain members of the selectin
ligand family. The same is true of the integrins and their
ligands. Because of this two-digit zip code (type of selec-
tin, type of integrin), there are enough “addresses” avail-
able to send the many different immune system cells to
all the right places. By equipping immune system cells
with different adhesion molecules, and by equipping
their intended destinations with the corresponding
adhesion partners, Mother Nature makes sure that the
different types of immune system cells will roll, stop,
and exit the blood exactly where they are needed.
N ATURAL KILLER CELLS
In addition to the complement system and the profes-
sional phagocytes, there is a third important player on the
innate immune system team – the natural killer (NK) cell.
Natural killer cells are descended from blood stem cells,
as are all the rest of the blood cells, and although natural
killer cells are members of the “lymphocyte” family –
together with B cells and T cells – NK cells do not have
receptors which are made by mixing and matching gene
segments. Natural killer cells mature in the bone marrow
as do B cells, but NK cells are short lived, with a half-life
of only about a week.
NK cells are not sentinel cells like macrophages, which
hang out in our tissues and wait for invaders. Indeed,
very few NK cells are found in tissues that are not under
attack. Like neutrophils, NK cells are “on call,” and most
NK cells are found in the blood or in the spleen and liver
(two organs that store blood). Natural killer cells use the
“roll, stop, exit” strategy to leave the blood and enter
tissues at sites of infection, and once in the tissues, NK
cells proliferate rapidly to build up their numbers. When
they reach the battleground, natural killer cells can play
two roles in defending us against infections. First, when
NK cells receive battle signals from other immune
system cells, they can give off cytokines that help with
the defense.
In addition to functioning as cytokine factories, natural
killer cells can destroy tumor cells, virus-infected cells,
bacteria, parasites, and fungi. NK cells kill these cells
by forcing them to commit suicide. In some cases, NK
cells employ an “injection system” that uses perforin pro-
teins to deliver “suicide” enzymes (e.g., granzyme B) into
a target cell. In other situations, a protein called Fas ligand
on the NK cell surface interacts with a protein called Fas
on the surface of its target, signaling the target cell to
self-destruct.
The method NK cells employ to identify their targets
is quite different from that of killer T cells. Natural killer
cells have no T cell receptors, but they have two other
types of receptors on their surface: “activating” receptors
which, when engaged, motivate the NK cell to kill; and
“inhibitory” receptors which, when engaged, encourage
it not to kill.
"kill"!
TARGET CELL NK CELL
"don't kill"!!
MHC I
The “don’t kill” signal is conveyed by receptors that
recognize class I MHC molecules on the surface of a
potential target cell. Class I MHC molecules are found in
varying amounts on the surface of most healthy cells in
our bodies. Consequently, the presence of this surface
molecule is an indication that a cell is doing okay. In
contrast, the “kill” signals involve interactions between
the activating receptors on the surface of an NK cell and
unusual carbohydrates or proteins on the surface of a
target cell. These peculiar surface molecules act as flags
which indicate that the target cell has been “stressed,”
usually because it has been infected with a virus or is
becoming cancerous. It is the balance between the “kill”
and the “don’t kill” signals which determines whether
NK cells will destroy a target cell.
Now, why do you think it would be a good idea to have
NK cells destroy target cells that do not express class I
MHC molecules? You remember that by examining pep-
tides displayed by class I MHC proteins, killer T cells are