Lymphocyte development and survival chapter 7
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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

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Lymphocyte development and survival Chapter 7

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Lymphocyte development and survivalChapter 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


Testing for appropriate antigen recognition properties (tolerance to self)

Activation by antigen

Differentiation

Major stages of development in lymphocytes

Expression of antigen receptor


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


RAG

B cell development: Expression of Ig


B cell development: Expression of Ig

  • Rescue of B cells with nonproductive rearrangments


Testing for appropriate antigen recognition properties (tolerance to self)

B cell development

Expression of antigen receptor

  • 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


Testing for appropriate antigen recognition properties (tolerance to self)

Activation by antigen

B cell development

Expression of antigen receptor


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


Testing for appropriate antigen recognition properties (tolerance to self)

Activation by antigen

Differentiation

B cell development

Expression of antigen receptor


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


Testing for appropriate antigen recognition properties (tolerance to self)

Activation by antigen

Differentiation

T cell development

Expression of antigen receptor


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


Testing for appropriate antigen recognition properties (tolerance to self)

T cell development

Expression of TCR


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?


Testing for appropriate antigen recognition properties (tolerance to self)

Activation by antigen

T cell development

Expression of TCR


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


Testing for appropriate antigen recognition properties (tolerance to self)

Activation by antigen

Differentiation

T cell development

Expression of TCR


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


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