DIFFERENTIATION AND MATURATION OF T CELLS IN THE THYMUS
REGULATED T-CELL DIFFERENTIATION
pre T cellpro T cell
immature T cell
NO ANTIGEN RECOGNIZING RECEPTOR
SIGNALING RECEPTOR
ANTIGEN RECOGNIZING RECEPTOR
preT-CD4+CD8+
TCR
Epithelial cellAPC
T- CELL DEVELOPMENT
NK cellNo
rearrangement
Lymphoid precursor
Pro-T
-rearrangementT
Pre-T
-rearrangement
Pre-T
Selectionclonal deletion
TT
TMature-T Mature-B
c-kit/CD44
H rearrangement
Surrogate L
L rearrangement
Selectionclonal deletion
B
B
BB
Pro-B
Pre-B
RAG-1/RAG-2
1. Generation of NK cells – no TCR
2. Differentiation of γδ and αβ TCR carrying T cells
3. Selection of αβ TCR – positive selection – negative selection
4. Differentiation of CD4+ and CD8+ T cell lineages
EVENTS OF T CELL DIFFERENTIATION IN THE THYMUS
Early pre-T Pre-Tα-chain
Lck signal
β rearrangement
γδ T-cellNo selection
αβ NKT-cell
αβCD4+ αβCD8+
CD4+CD8+
IL-7-dependent proliferation
Pro-T
unsuccesful β-chain
unsuccesful α-chainno positive selectionnegative selection
α rearrangement
Late pre-TCD4+CD8+
++
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 TOLERANCE5. Focusing the T cell repertoire for
recognition of non self6. CD4+ and CD8+ T cell use the same TCR
repertoire7. Individualized T cell repertoire
available in the periphery8. CD4 and CD8 co-stimulatory molecules
are involved in positive selection
αβTCR αβTCRCD4+ CD8+
SELECTION OF T LYMPHOCYTES IN THE THYMUS
UNDER THE CAPSULE
CORTEX
CORTEX/MEDULLA
IL-7-dependent proliferation
β+preTαCD4-CD8-
DN
CD4+CD8+DP
MEDULLA
TCRαβ
TCR(-) sMHC+sP sMHC+fP fMHC+fP
selection
– selection
–AICD
NO
PERIPHERAL TOLERANCE
AICD – Activation Induced Apoptosis
CD4+CD8+ CD4+CD8+
POSITIVE SELECTION OF DOUBLE POSITIVE (DP) T CELLS ALSO DIRECTS CD4 AND CD8 SINGLE POSITIVE (SP)T CELL COMMITMENT
MHC-II + peptide complexes recruit CD4
Thymic epithelial cell
MHC-I + peptide complexes recruit CD8
BARE LYMPHOCYTE SYNDROME (BLS)
Lack of MHC class I – no CD8+ cells Lack of MHC class II – no CD4+ cells
POSITIVE SELECTION FOR 3 – 4 DAYS, SUCCESSIVE α-GENE REARRANGEMENTS
POSITIVE SELECTION – Thymic education (no instruction for specificity)Low avidity interaction of MHC - self peptide - TCR Thymic epithelial cellsSelf peptide composition and concentration (foreign peptides are not present)Low peptide dose induces positive selection – special ligands80-90% of DN (CD4-CD8-) T cells is NOT positively selected PASSIVE CELL DEATH BY NEGLECTION
NEGATIVE SELECTION – Central self toleranceHigh avidity of MHC - self peptide - TCR interactionUbiquitous and abundant self antigens are present in the thymusHigh peptide dose induces negative selectionAny 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 REPERTOIREPHYSIOLOGICAL TRESHOLD
NOT COMPLETE
SELECTION OF THE T CELL REPERTOIRE – CENTRAL TOLERANCE
Homozygote Heterozygote
HOMEOSTASIS OF POSITIVE AND NEGATIVE SELECTION IN THE DEVELOPMENT OF THE AVAILABLE T LYMPHOCYTE REPERTOIRE
Number of MHC molecules
Ratio of positive selection
Ratio of negative selection increases with the number of MHC genes
Activated T-cellMature naive T-cell
Memory T-cell
T-CELL DIFFERENTIATION IN THE PERIPHERY
Ag
Ag
CD4 TCR
APC
CD8 TCR
APCCD4 TCR
APC
CD8 TCR
APC
CD4 TCR
APC
CD8 TCR
APC
Ag
Normal tissue cells do not express MHC class IINO SIGNAL 1. for CD4+ Th activation
Normal tissue cells do not express co-stimulatory molecules and do not produce T cell differentiating cytokinesNO SIGNAL 2. for CD4+ Th activation
Migration of naive T lymphocytes to normal tissues is limitedAntigen presenting cells are not activated in normal tissues
NO SIGNAL 3. for CD4+ Th activation
PERIPHERAL TISSUES TOLERIZE THEMSELVES
PERIPHERAL TOLERANCEIMMUNE RESPONSES ARE NOT INITIATED IN THE PERIPHERY
ANERGY – Functional unresponsiveness, no IL-2 secretion
SIGNAL 1 Recognition of auto-antigen on tissue cellSIGNAL 2 No B7 and CD40 expression, no co-stimulation
Tissue resident professional APC are not activated SIGNAL 3 Innate immunity is not activated
No inflammation
CLONAL DELETION – Activation induced cell deathRequires persistant high antigen dose Fas – FasL interaction
SUPPRESSION – Activity of other cells Cytokine-mediated balance Effector functions are inhibited by regulatory T cells
CLONAL IGNORANCENo contact with the immune system
Immunologically privileged sites Central nervous system, eye
No recognition in the periphery
MECHANISMS OF PERIPHERAL TOLERANCE
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