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 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

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

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

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 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: 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

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