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Lymphocyte Development and Structure

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Topic updated on 08/07/17 11:51am

Introduction
  • Lymphocyte development is complex and has several features including
    • localization to primary lymphoid organs such as
      • the bone marrow for B-cell development
      • the thymus for T-cell development
    • VDJ recombination in order to
      • rearrange genetic material
      • generate a unique B- or T-cell receptor
    • positive selection in order to
      • ensure all cells have functional receptors
    • proliferation in order to
      • expand the pool of potential lymphocytes
      • allow for broad protection against different types of antigens
    • negative selection in order to
      • remove cells that target self-antigens
      • protect against autoimmunity
  • There are many mechanisms to increase diversity during lymphocyte development such as
    • random recombination of genetic material during
      • VDJ recombination
    • random nucleotide addition to hypervariable regions by
      • the protein TdT
    • random assortment of different chains in receptor assembly
      • heavy chains with light chains in B-cells
      • alpha chains with beta chains in T-cells
    • somatic hypermuation after antigen exposure
      • only occurs in B-cells
B-Cell Development
  • B-cells develop in the bone marrow
    • develop a unique B-cell receptor
    • are tested to ensure that the receptor is functional
    • are further tested for self-reactivity to prevent autoimmunity
  • This development cycle is coordinated by the orderly progression through stages where
    • supporting cells give feedback at every stage
    • interaction strength of the B-cell receptor is monitored
Stages of B-Cell Development
Cell Type
Developmental Steps
Surface Receptor
Associations
Lymphoid stem cell
  • Commitment to B-cell lineage
  • None
  • Pleuripotent
Pro B-cell
  • Heavy chain VDJ recombination
  • Additional diversity from TdT modification
  • Heavy chain only
  • Recombination mediated by RAG proteins
  • Defect in RAG leads to Omenn syndrome with no mature B cells
Pre B-cell
  • Allelic exclusion to ensure only one heavy chain expressed
  • Positive selection
  • Proliferation
  • Pre B-cell receptor
  • Key step in monitoring activity of the recombined heavy chain
Immature B-cell
  • Light chain VJ recombination
  • Negative selection
  • IgM receptor
  • Inactivation of recombination machinery
  • Key step in tolerance
Mature B-cell
  • Exit into blood stream
  • IgM receptor
  • IgD receptor
  • Circulates and awaits activation by antigen
T-Cell Development  
 

 
  • T-cells migrate from the bone marrow to the thymus where they
    • develop a unique T-cell receptor
    • are tested to ensure that the receptor is functional
    • are further tested for self-reactivity to prevent autoimmunity
  • This development cycle is coordinated by the orderly progression through stages where
    • supporting cells give feedback at every stage
    • receptors that bind too strongly lead to developing T-cell death
    • the T-cell receptor undergoes selection in distinct compartments
Stages of T-Cell Development
Cell Type
Developmental Steps
Surface Proteins
Associations
T-cell precursor
  • Commitment to T-cell lineage
  • Migration to thymus
  • None
  • Lack of thymic development in DiGeorge syndrome
Double negative
  • Rearrangement of the β T-cell receptor chain
  • Proliferation
  • Pre T-cell receptor
  • Occurs in the thymic cortex
Double positive
  • Rearrangement of the α T-cell receptor chain
  • Expression of both CD4 and CD8
  • Positive selection against both class I and class II MHC
  • CD4
  • CD8
  • T-cell receptor
  • Key step in determining type of T-cell that develops
  • MHC II binding leads to CD4+ cells
  • MHC I binding leds to CD8+ cells
Single positive
  • Migration to medulla of thymus
  • Negative selection against self antigens
  • T-cell receptor
  • Either CD4 or CD8
  • The transcription factor AIRE allows medullary cells to express proteins from all areas of body
  • This ensure tolerance to vast majority of self antigens
Mature T-cell
  • Exit into blood stream
  • Awaits peripheral activation
  • T-cell receptor
  • Either CD4 or CD8
  • Circulates and awaits activation by antigen


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(M1.IM.74) A thymic sample from a fetus is examined. One cell type found was double-positive for the CD4 and CD8 receptors. What is the identity of these double-positive cells? Topic Review Topic

1. T-cell progenitors cells in the bone marrow
2. B-cells
3. Immature T-cells of the thymic cortex
4. Immature T-cells of the thymic medulla
5. Macrophages

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