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