Download T-cell maturation

Dr.Fadwa Al-Ghalib
Immunology
T-cell maturation and selection
2nd year 2011
T-Cell production and maturation
THYMUS:
 The Thymus is a lymphoid organ in the upper anterior thorax , above the heart.
 It contains a multilobed organ which are divided into outer region The Cortex and
the inner Medulla.
Anatomical Organization of the Thymus
• The epithelial nurse cells are in the outer cortex
•
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).
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Dr.Fadwa Al-Ghalib
Immunology
T-cell maturation and selection
2nd year 2011
 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  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  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  TCR
2. Most of thymic lymphocytes differentiate into βTCR cells which account >95%
of T- lymphocytes found in the secondary lymphoid tissue and in the circulation.
T-Cell surface diversity (β & )
 T cells express either β (95% of T cells) or  TCR for their whole life
span.
 The earliest T cells seen during fetal development express  TCR.
 It is believed that if  and  are productively rearranged first, the cell will
probably become a  T cell.
 If β is productively rearranged first and expressed on the membrane with
surrogate  chain (pT), the cell will usually go on to rearrange a chain
gene segments and become an β T cell.
 Less than 5% of peripheral T cells have  TCRs
 but they are the major type of T cells in skin, intestinal epithelium and
pulmonary epithelium
 TCR
These T cells having  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+.
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Dr.Fadwa Al-Ghalib
Immunology
T-cell maturation and selection
2nd year 2011
The  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,, and  T-cell receptor gene. production of 
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 -chain genes.
• Express an :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:
•
•
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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.
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.
a- 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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Dr.Fadwa Al-Ghalib
Immunology
T-cell maturation and selection
2nd year 2011
b- 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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Dr.Fadwa Al-Ghalib
Immunology
T-cell maturation and selection
5
2nd year 2011