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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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


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Hematopoiesis

  • Lymphopoiesis mainly occurs in central lymphoid tissues


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Testing for appropriate antigen recognition properties (tolerance to self)

Activation by antigen

Differentiation

Major stages of development in lymphocytes

Expression of antigen receptor




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B cell development

Expression of antigen receptor (immunoglobulin)


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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)





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RAG

B cell development: Expression of Ig


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B cell development: Expression of Ig

  • Rescue of B cells with nonproductive rearrangments


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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



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B cell development: Negative selection

  • Self-reactive B cells may undergo further light chain rearrangement


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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


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Testing for appropriate antigen recognition properties (tolerance to self)

Activation by antigen

B cell development

Expression of antigen receptor



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B cell development: activation by antigen

  • Chemokines attract and retain B cells in the lymph nodes

    • CXCL13



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Testing for appropriate antigen recognition properties (tolerance to self)

Activation by antigen

Differentiation

B cell development

Expression of antigen receptor


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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


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B cell cancers

  • B cell tumors arise from cells at various stages of development

  • Retain characteristics of the normal B cell equivalent





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Testing for appropriate antigen recognition properties (tolerance to self)

Activation by antigen

Differentiation

T cell development

Expression of antigen receptor


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T cell development

Expression of TCR


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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





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Testing for appropriate antigen recognition properties (tolerance to self)

T cell development

Expression of TCR


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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






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Mechanisms of positive and negative selection

  • Mechanisms that differentiate positive and negative selection are not clear

    • Difference in affinity?

    • Other signals required?


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Testing for appropriate antigen recognition properties (tolerance to self)

Activation by antigen

T cell development

Expression of TCR



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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


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Testing for appropriate antigen recognition properties (tolerance to self)

Activation by antigen

Differentiation

T cell development

Expression of TCR


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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



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