Lymphocyte Development

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

lymphocytesExpression of antigen

receptor

Activation by antigen

Differentiation

Testing for appropriate antigen recognition

properties (tolerance to self)

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

Activation by antigen

Testing for appropriate antigen recognition

properties (tolerance to self)

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

Activation by antigen

Differentiation

Testing for appropriate antigen recognition

properties (tolerance to self)

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

Activation by antigen

Differentiation

Testing for appropriate antigen recognition

properties (tolerance to self)

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 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

Activation by antigen

Testing for appropriate antigen recognition

properties (tolerance to self)

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

Activation by antigen

Differentiation

Testing for appropriate antigen recognition

properties (tolerance to self)

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