T-cell production and maturation thymus




Дата канвертавання27.04.2016
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Dr.Fadwa Al-Ghalib Immunology 2nd year 2011

T-cell maturation and selection




T-Cell production and maturation

THYMUS:

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


Anatomical Organization of the Thymus




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




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




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




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




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



Maturation of T cells

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



  • Changes in the status of the T-cell receptor genes

  • Expression of the T- cell receptor protein

  • Production of other T-cell surface glycoproteins (essential for receptor’s full function, such as CD4,CD8 and CD3 complex).


Phenotypic Variations of T-cell during maturation

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



1- Stage 1 ( early thymocytes), Double –negative cells:

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




  • 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).



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




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




  • They are 3% of the cells in the thymus.


2- Stage II (Intermediate) thymocytes, Double-positive Cells:

  • expressing CD1+, CD44-,CD25-

  • At this stage, the cells develop the CD3:TCR complex, CD4 and CD8.

  • Therefore the cells are CD3:pTa:b+,CD4+,CD8+.

  • Genes encoding the TCR a chain are rearranged in this stage

  • They are about 80% of cells in the thymus.


3- Stage III (mature) thymocytes.

Show major phenotypic changes;



  • Loss of CD1

  • cell surface CD3 is associated with high density ba TCR

  • mature T cells express either CD4 or CD8



There are at least two pathways of T-cell differentiation in the thymus:


  1. Less than 1% of mature thymic lymphocytes express the dg TCR

  2. Most of thymic lymphocytes differentiate into aβTCR cells which account >95% of T- lymphocytes found in the secondary lymphoid tissue and in the circulation.


T-Cell surface diversity (aβ & dg)

    • T cells express either aβ (95% of T cells) or dg TCR for their whole life span.

    • The earliest T cells seen during fetal development express dg TCR.

    • It is believed that if g and d are productively rearranged first, the cell will probably become a dg T cell.

    • 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.

    • Less than 5% of peripheral T cells have dg TCRs




dg TCR

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




  1. One population, the intraepidermal lymphocytes, are found in the skin and are CD4- 8- (double-negative).

  2. 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.


The development of T cells in the Thymus
1)---Subcapsular region:

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.


2)---Cortex (Positive selection).

  • DP thymocytes rearrange their a-chain genes.

  • Express an a:βT-cell receptor & CD3 complex, become sensitive to interaction with self-peptide:self:MHC complexes.

  • DP –cells undergo positive selection in thymus cortex via contact with cortical epithelial cells.

What is the role of Thymic Cortical Cells in positive selection?

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

Either:

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:


  • DP cells die within 3-4 days unless they recognize pMHC-I or pMHC-II on cortical epithelial cells in the cortical region.

  • Thymocytes surviving positive selection express only CD4 or CD8 in addition to CD3 and TCR.

  • The developing double- positive cell will become a single positive cell and retains either CD4 or CD8.

  • Retention of a co-receptor is based on which class of MHC molecules is recognized by the TCR.



3)---Cortico-medullary junction (Negative Selection)

  • DP cells undergo negative selection for self-reactivity.

  • Occurrs at the cortico-medullary junction.

  • Nearly mature thymocytes encounter a high density of dendritic cells.




  1. Medullary thymocytes that interact strongly with self peptides on MHC-I or MHC-II of APC (macrophages & dendritic cells) undergo apoptosis.

  2. 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



4)---Medulla:

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



§ Only 1-2% of the cells in the thymus pass both selection procedures and are allowed to continue maturation






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