Lymphocyte development

and survival

Chapter 7
 Objectives
• Describe or construct flow charts showing the
stages in development of B cells and T cells,
including:
– The general characteristics (surface
markers, etc) of lymphocytes at each stage
– Other types of cells or cytokines that are
required at each stage
– What happens to cells which fail to complete
a stage of development
• Predict how specific genetic defects would
alter lymphocyte development
 Hematopoiesis

•Lymphopoiesis mainly occurs in

central lymphoid tissues
Major stages of development in
lymphocytes
Expression of antigen receptor

Testing for appropriate

antigen recognition properties
(tolerance to self)

Activation by antigen

Differentiation
Overview of B cell development
Overview of T cell development
B cell development
Expression of antigen receptor
(immunoglobulin)
B cell development: Expression of Ig

• Stromal cells in the bone marrow provide cytokines and

support required for early B cell development
– Interleukin-7 (IL-7)
– Cell adhesion molecules (CAMs)
B cell development: Expression of Ig
B cell development: Expression of Ig
B cell development: Expression of Ig
B cell development: Expression of Ig

RAG
B cell development: Expression of Ig
•Rescue of B cells with nonproductive rearrangments
 B cell development

Expression of antigen receptor

Testing for appropriate

antigen recognition properties
(tolerance to self)

• Negative selection: selection of cells that do NOT

bind to self antigens
B cell development: Negative selection
B cell development: Negative selection
• Self-reactive B
cells may undergo
further light
chain
rearrangement
B cell development: Negative selection

• Some self antigens are only expressed in the

periphery

• High levels of cross-linking antigen in periphery

can induce B cell anergy
B cell development

Expression of antigen receptor

Testing for appropriate

antigen recognition properties
(tolerance to self)

Activation by antigen
B cell development: activation by
antigen
 B cell development: activation by
antigen
• Chemokines attract and retain B cells in the lymph nodes
–CXCL13
B cell development: activation by
antigen
B cell development

Expression of antigen receptor

Testing for appropriate

antigen recognition properties
(tolerance to self)

Activation by antigen

Differentiation
B cell development: differentiation

• Activated B cells undergo clonal expansion

• Progeny differentiate into plasma cells or

memory B cells
– Isotype switching and somatic
hypermutation occur
 B cell cancers
• B cell tumors arise
from cells at various
stages of
development

• Retain characteristics
of the normal B cell
equivalent
Overview of T cell development
Some lymphoid progenitors migrate
to the thymus
The importance of the thymus for T
cell development
T cell development

Expression of antigen receptor

Testing for appropriate

antigen recognition properties
(tolerance to self)

Activation by antigen

Differentiation
T cell development

Expression of TCR
T cell development: expression of TCR

• Progenitors arriving from

the bone marrow do not
express TCR, CD3, CD4, or
CD8

• Successful rearrangement of
TCR β chain results in
expression of a pre-T-cell
receptor, CD3, CD4, and CD8
T cell development: expression of TCR
T cell development: expression of TCR
T cell development: expression of TCR
T cell development

Expression of TCR

Testing for appropriate

antigen recognition properties
(tolerance to self)
T cell development: selection for
self-tolerance
• Selection for self-tolerance in T cells
requires two stages:

– Positive selection for ability to bind to

MHC : peptide complexes

– Negative selection eliminates T cells with

high-affinity binding to MHC : self peptide
complexes
T cell development: Positive selection
T cell development: Positive selection
T cell development: Negative selection
The role of thymic cells in positive
and negative selection
 Mechanisms of positive and negative
selection
•Mechanisms that
differentiate positive
and negative selection
are not clear
– Difference in
affinity?
– Other signals
required?
T cell development

Expression of TCR

Testing for appropriate

antigen recognition properties
(tolerance to self)

Activation by antigen
T cell development: activation by
antigen
 T cell development: activation by
antigen
• As with B cells, self-reactive T cells can also be
eliminated in the periphery
–Activation-induced cell death
–Anergy
T cell development

Expression of TCR

Testing for appropriate

antigen recognition properties
(tolerance to self)

Activation by antigen

Differentiation
T cell development: differentiation

• Activated T cells undergo clonal expansion

• Differentiation of progeny into effector or

memory cells
– Cytotoxic T lymphocytes
– Helper T cells (Th1, Th2)
– Memory T cells
T cell cancers