T-cell production and maturation thymus

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  The Thymus is a lymphoid organ in the upper anterior thorax , above the heart.
  

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  It contains a multilobed organ which are divided into outer region The Cortex and the inner Medulla.
  

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  The epithelial nurse cells are in the outer cortex
  

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  The Cortex contains epithelial cells and many immature thymocytes with a few macrophages.
  

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  The corticomedullary junction contains interdigitating dendretic cells (IDC) and macrophages
  

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  The Medulla contains epithelial cells, mature thymocytes, lots of macrophages and dendritic cells.
  

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  Epithelial cells and IDCs and macrophages express MHC class II molecules which are crucial to T-cell development and selection.
  

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  Hassall’s corpusculs are found in the thymic medulla. Their function is unknown.Appear to contain degenerating epithelial cells.
  

Maturation of thymocytes into mature T cells occur in distinct stages:

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  Changes in the status of the T-cell receptor genes
  
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  Expression of the T- cell receptor protein
  
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  Production of other T-cell surface glycoproteins (essential for receptor’s full function, such as CD4,CD8 and CD3 complex).
  

After T cells enter the thymus they begin to proliferate and differentiate into what will be the T cells

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  These are the cells which enter the subcapsular region of the thymus, arriving as pre-T cells from the bone marrow. (progenitor cells)
  

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  In this region, progenitor cells interact with thymic stromal cells, they get signaled to proliferate, within a week they express certain T-cell specific glycoproteins, such as: CD44(adhesion molecule), CD25 (receptor for IL-2).
  

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  At this stage, they do not express TCR complex or the co-receptors CD4 &CD8. (therefore CD4-, CD8- are = double negative).
  

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  These cells develop into large, actively proliferating, self-renewing lymphoblasts which generate the thymocyte population.
  

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  They are 3% of the cells in the thymus.
  

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  expressing CD1+, CD44-,CD25-
  
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  At this stage, the cells develop the CD3:TCR complex, CD4 and CD8.
  
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  Therefore the cells are CD3:pTa:b+,CD4+,CD8+.
  
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  Genes encoding the TCR a chain are rearranged in this stage
  
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  They are about 80% of cells in the thymus.
  

Show major phenotypic changes;

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  Loss of CD1
  
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  cell surface CD3 is associated with high density ba TCR
  
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  mature T cells express either CD4 or CD8
  

1. 
   Less than 1% of mature thymic lymphocytes express the dg TCR
   
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   Most of thymic lymphocytes differentiate into aβTCR cells which account >95% of T- lymphocytes found in the secondary lymphoid tissue and in the circulation.
   

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  T cells express either aβ (95% of T cells) or dg TCR for their whole life span.
  
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  The earliest T cells seen during fetal development express dg TCR.
  
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  It is believed that if g and d are productively rearranged first, the cell will probably become a dg T cell.
  
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  If β is productively rearranged first and expressed on the membrane with surrogate a chain (pTa), the cell will usually go on to rearrange a chain gene segments and become an aβ T cell.
  
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  Less than 5% of peripheral T cells have dg TCRs
  

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  but they are the major type of T cells in skin, intestinal epithelium and pulmonary epithelium
  

These T cells having dg TCR are distributed in two populations.

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   One population, the intraepidermal lymphocytes, are found in the skin and are CD4- 8- (double-negative).
   
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   The other population, the intraepithelial lymphocytes, are found in the intestinal epithelium and are CD8+.
   

The dg TCRs are characterized by limited diversity. Some of these cells can bind antigens directly, without the mediation of MHC molecules.

Thymocytes enter from blood to the subcapsular region. Are known as double-negative thymocytes. (they don’t express the Ag receptor: CD3 complex, CD4 &CD8 co-receptors. These cells proliferate, rearrange their β,g, and d T-cell receptor gene.® production of dg cells & cells expressing the pre-T-cell receptor. Finally producing double- positive cells (DP) for CD4 & CD8.

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  DP thymocytes rearrange their a-chain genes.
  
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  Express an a:βT-cell receptor & CD3 complex, become sensitive to interaction with self-peptide:self:MHC complexes.
  
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  DP –cells undergo positive selection in thymus cortex via contact with cortical epithelial cells.
  

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  Is to ask the thymocytes if they can recognize/bind self Ag-MHC?.
  

A- if the cell cannot recognize the MHC molecules on the surface of the thymic cortical epithelial cells, it “fails” positive selection and dies.

B- if it recognizes self-MHC, it “ passes” positive selection.
Positive Selection:

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  DP cells die within 3-4 days unless they recognize pMHC-I or pMHC-II on cortical epithelial cells in the cortical region.
  
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  Thymocytes surviving positive selection express only CD4 or CD8 in addition to CD3 and TCR.
  
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  The developing double- positive cell will become a single positive cell and retains either CD4 or CD8.
  
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  Retention of a co-receptor is based on which class of MHC molecules is recognized by the TCR.
  

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  DP cells undergo negative selection for self-reactivity.
  
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  Occurrs at the cortico-medullary junction.
  
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  Nearly mature thymocytes encounter a high density of dendritic cells.
  

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   Medullary thymocytes that interact strongly with self peptides on MHC-I or MHC-II of APC (macrophages & dendritic cells) undergo apoptosis.
   
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   If a developing CD4+, CD8+ T cell does not recognize any peptide/MHC complex it too will be induced to undergo apoptosis
   

This is called : Negative Selection

Thymocytes that survive both positive and negative selection leave the thymus in the blood as mature single positive CD4 or CD8 T cells and enter the circulation