differentiation and maturation of t cells in the thymus
DESCRIPTION
DIFFERENTIATION AND MATURATION OF T CELLS IN THE THYMUS. BONE MARROW. HSC. HEMATOPOIETIC STEM CELL. THYMUS. LYMPHOID PRECURSOR. MYELOID PRECURSOR. BLOOD. BLOOD. B-cell. NK-cell. T-cell. monocyte. mast. neutrophil. DC. TISSUES. LYMPHOID TISSUES. B-cell. T-cell. mackrophage. - PowerPoint PPT PresentationTRANSCRIPT
DIFFERENTIATION AND MATURATION OF T CELLS IN THE THYMUS
DC mackrophage
MYELOID PRECURSOR
BONE MARROW
HSC HEMATOPOIETIC STEM CELL
mast
DC monocyte neutrophilmast
neutrophil
TISSUES
BLOOD
B-cell T-cell
T-cellNK-cell
THYMUS
B-cell
LYMPHOIDPRECURSOR
LYMPHOID TISSUES
BLOOD
T- CELL DEVELOPMENT
NK cell
Pro-T
-rearrangementT
Pre-T
-rearrangement
Pre-T
Selectionclonal deletion
TT
TMature-T
Lymphoid precursor
Mature-B
c-kit/CD44
H rearrangement
Surrogate L
L rearrangement
Selectionclonal deletion
B
B
B
B
Pro-B
Pre-B
RAG-1/RAG-2
REGULATED T-CEREGULATED T-CELLL DIFFERENTIATIONL DIFFERENTIATION
pre T cellpro T cell
immature T cell
NO ANTIGEN RECOGNIZING RECEPTOR
SIGNALING RECEPTOR
ANTIGEN RECOGNIZING RECEPTOR
preT-CD4+CD8+
TCR
Epithelial cellAPC
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 clones4. Elimination of self agressive
clones (-)5. CENTRAL TOLERANCE6. Focusing The T cell repertoire
for recognition of non self7. Individualized T cell repertoire
is available in the periphery 8. 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
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
EFFECTOR T CELLS
Cytotoxic T cells Th1 cells Th2 T cells
Virus infected cellMacrophage
containing bacteriaB cell presenting specific antigen
CytotoxinsPerforin
Granzyme
CytokinesFasLIFNγ
TNF-βTNF-α
ActivationIFNγ
GM-CSFTNF-αCD40LFasL
CytokinesIL-3
GM-CSFIL-10TGFβ
Eotaxin
ActivationIL-4IL-5
CD40L
CytokinesIL-3
TNF-βIL-2
EFFECTOR T LYMPHOCYTES
Effector T cells interact with and act on antigen presenting cells
Effector T cells secrete cytokines and cytotoxins
B-cell T-cell
Appearance of antigen Soluble, molecules on the surface of any cell, particles
Cells carrying self MHC-antigen derived peptide complexes
Nature of the antigén Natíve protein, carbohydrate, lipids, metals,any structure
Processed protein fragments = peptides
Ligand Conformational determinantsequential determinant
MHC-peptide complex
Antigen recognizing receptor on the cell surface
variable BCRligand (antigen) specificbivalent
variable TCR MHC + peptide pecificmonovalent
Soluble antigen recognizing receptor
antibody -
Collaboration of other cells - Antigen processing and presenting cells APC
Antigen processing, presentation
- Intracellular enzymatic degradation, peptide transportation
Result of full activation Production of effector molecule (antibody= soluble BCR)
Activation of new genesproduction of lymphokines
Possibililties of cell activation FULLDifferentiation to plasma cell, antibody productionPARTIAL funcional anergyAPOPTOSIS
FULLLimphokine productionPARTIAL functional anergyproduction of certain lymphokinesAPOPTOSIS
Co-receptors CD19, CD21, CD22 CD4, CD8, CD28/CTLA4, CD2, CD38