T-cell development central tolerance

The cellular organization of the thymus

The proportion of the thymus that produces T cells decreases with age.

DIFFERENTIATION AND MATURATION OF T CELLS IN THE THYMUS

Commitment to the T-cell lineage changes receptor expression

Lack of IL7 signaling(IL7 or IL7R) stalls

Early T-cell developmentSCIDs

T-cell development is driven by the receptor Notch 1.

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

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.

•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

γδ T-cells

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

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T cell development and migration in the thymus.

8-1_T_Cell_Development.wmv

Only a small fraction of T cells mature into functional T cells

Positive selection:Occurs in the cortex, requires thymic epithelial cells (MHCI/MHCII positive)

-Az αβ double-positive Thymocytes must recognize self-MHC.- First step, (Ca 2% of thymocytes survive!!)

- Selection occurs in 3-4 days!!

Positive selection --- results in clones that are reactive to self MHC. Basis of MHC restriction!!!Peptides are recognized in the context of self MHC

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 REARRANGEMENTSBARE LYMPHOCYTE SYNDROME (BLS)

Lack of MHC class I – no CD8+ cells Lack of MHC class II – no CD4+ cells

Negative selection of T cells in the thymus.

• Elimination of potentially autoreactive clones.• Requires several cell types besides epithelial cells: for example DC or macrophages• In summary:

development of central T cell tolerance is an integral part of T cell differentiation. T cells incapable of interacting with self-MHC/self-antigen complexes are eliminated during positive selection, whereas clones with intermediate or high affinity towards the same complexes will survive and become single-positive T cells. On the other hand, autoreactive clones with high affinity towards self-MHC/self-antigen complexes are eliminated during negative selection. An interesting cell type is the self-reactive regulatory T cells (Treg) that have high affinity TCRs, bordering at negative selection (B), and have important roles in maintaning peripheral tolerance (discussed later).

The response of the immune system to the stimuli of the outer and inner environment.

Immunological tolerance

Immunological tolerance

Definition:

Unresponsiveness to a given antigen induced by the interaction of that antigen with the lymphocytes;

Antigen specific!!! Unlike immunosuppresion.

Why is this important?

-All individuals are tolerant to their own antigens (self tolerance). -Failure of self tolerance results in autoimmunity.

-Terapeutic potential:Treat autoimmune diseases, allrgic reaction or even tissue rejection.

Central T cell tolerance

Central T cell is surprisingly effective mainly mediated by negative selectionHow can many tissue-restricted antigens (TRA) be expressed in medullary thymic epithelial cells (mTECs)?

Central and peripheral tolerance to self antigens.

Elimination of self-reactive clonesBUT!!! Some T-cell clones escape,

Elimination of „fugitive” or altered clones important role for regulatory T-cells.

Autoimmun regulator (AIRE)

AIRE is responsible for the expression of tissue antigens in the thymusMutations in AIRE cause an autoimmune polyendocrine syndrome

Lack of proper negative selection allows too many self reactive T-cell clones to leave the thymusAutoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)

Deficiency in establishing central T-cell tolerance:

Autoimmune PolyEndocrinopathy- Candidiasis-Ectodermal Dystrophy (APECED),

AIRE deficiency. AIRE: transcription factor inducing expression of many tissue-specific genes normally not expressed in the thymus.

Rare disease, but more frequently seen in inbred populations Finnish, Iranian Jews and in the island of Sardine

Symptoms of APECED

apeced

• 85% hypoparathyreodism• 75% adreal failure• 60% ovarian failure• 52% nail dystrophy• 18% diabetes mellitus

• 100% mucocutaeous canndidiasis (MCM)

• Anti-Th17 specific antibodies !!!!!

• Role of Th17 discovered by studying a rare immunodeficiency

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