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DIFFERENTIATION AND MATURATION OF T CELLS IN THE
THYMUS
The cellular organization of the thymus
The proportion of the thymus that produces
T cells decreases with age.
Commitment to the T-cell lineage changes receptor expression
Lack of IL7 signaling
(IL7 or IL7R) stalls
Early T-cell development
SCIDs
T-cell development is driven by the receptor Notch 1.
REGULATED T-CELL DIFFERENTIATION
preT-
Epithelial cell
CD4+CD8+
TCR
APC
immature T cell
pre T cell
pro T cell
NO ANTIGEN RECOGNIZING
RECEPTOR
SIGNALING RECEPTOR
ANTIGEN RECOGNIZING
RECEPTOR
α:β and γ:δ T cells develop from a common
double-negative T-cell progenitor.
Only a few percent of the
developing thymocytes lives,
the rest are eliminated by
apoptosis
T-cell receptor gene rearrangements in double-negative
thymocytes can lead to the expression of either a γ:δ receptor
or a pre-T-cell receptor.
Gene expression through the stages of α:β T-cell development in
developing T cells.
Nemazee Nature Reviews Immunology 6, 728–740 (October 2006) | doi:10.1038/nri1939
POSITIVE SELECTION OF DOUBLE POSITIVE (DP) T CELLS ALSO DIRECTS CD4 AND CD8
SINGLE POSITIVE (SP) T CELL COMMITMENT
POSITIVE SELECTION FOR 3 – 4 DAYS, SUCCESSIVE α-GENE REARRANGEMENTS
BARE LYMPHOCYTE SYNDROME (BLS)
Lack of MHC class I – no CD8+ cells
Lack of MHC class II – no CD4+ cells
SELECTION OF T LYMPHOCYTES IN THE THYMUS
UNDER THE
CAPSULE
IL-7-dependent proliferation
CORTEX
CD4-CD8DN
β+preTα
TCRαβ
TCR(-) sMHC+sP
sMHC+fP
CD4+CD8+
fMHC+fP
DP
selection
CORTEX/
MEDULLA
+

+

NO 
– selection
1. The primary T cell pool is biased to
MHC-specificity (V genes) 1-2% for one
allotype
2. Focusing the T cell pool to self MHC
recognition (+)
3. Elimination of useless and self
agressive clones (-)
4. CENTRAL TOLERANCE
5. Focusing the T cell repertoire for
recognition of non self
6. CD4+ and CD8+ T cell use the same TCR
repertoire
7. Individualized T cell repertoire
available in the periphery
8. CD4 and CD8 co-stimulatory molecules
are involved in positive selection
MEDULLA
–
AICD
AICD – Activation Induced
Apoptosis
αβTCR αβTCR
CD4+ CD8+
PERIPHERAL TOLERANCE
SELECTION OF THE T CELL REPERTOIRE – CENTRAL TOLERANCE
POSITIVE SELECTION – Thymic education (no instruction for specificity)
Low avidity interaction of MHC - self peptide - TCR
Thymic epithelial cells
Self peptide composition and concentration (foreign peptides are not present)
Low peptide dose induces positive selection – special ligands
80-90% of DN (CD4-CD8-) T cells is NOT positively selected
PASSIVE CELL DEATH BY NEGLECT
NEGATIVE SELECTION – Central self tolerance
High avidity of MHC - self peptide - TCR interaction
Ubiquitous and abundant self antigens are present in the thymus
High peptide dose induces negative selection
Any thymic antigen presenting cell: epithelial cells, bone marrow-derived
macrophages, dendritic cells
THE GENERATION OF SELF MHC + FOREIGN PEPTIDE SPECIFIC T CELLS REQUIRES
WEAK INTERACTION WITH SELF MHC + SELF
PEPTIDE
SELF RESTRICTED AND TOLERANT PERIPHERAL T CELL REPERTOIRE
PHYSIOLOGICAL TRESHOLD
NOT COMPLETE
γδ T-cells
•MHC-independent, CD1c and CD1d dependent
•Double megative
•comprise up to 50% of the intra-epithelial lymphocyte population
•expandedinintracellularbacterialinfections(Mycobacterium tuberculosis and Listeriamonocytogenes),
extracellularinfections (Borreliaburgdorferi)
•a population that is expanded in certain disease states such as celiac disease