The development of regulatory T (Treg) cells is essential for the maintenance of immune tolerance and homeostasis. In the thymus, TCR-specificity to self-antigen appears to be a primary determinant for Treg cell lineage commitment, imprinting both self and foreign antigens in the peripheral Treg cell population to provide dominant tolerance. The degree of T cell self-reactivity considered dangerous by the immune system, thereby requiring thymic education to prevent autoimmunity, is unknown.

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... , I analyzed a panel of TCRs with a broad range of reactivity to ovalbumin (OVA 323-339 ) in the RIP-mOVA self-antigen model for their ability to induce mechanisms of thymic tolerance. Thymic Treg cell generation in vivo was directly correlated with reactivity to OVA-peptide in a broad ~1,000-fold range, and its developmental "niche size" was unexpectedly dependent on TCR affinity. The threshold for Treg cell differentiation was almost 100-fold lower than that required for eliciting thymic negative selection and peripheral T cell responses. Thus, these data suggest that Treg cell differentiation is a default outcome of self-antigen encounter for CD4 + thymocytes, and that thymic tolerance mechanisms are tuned to limit the escape of self-reactive effectors without Treg cell chaperones into the periphery. In addition, in the study of developmental stage of Treg cells, I demonstrated that differentiation of most Treg cells occurs at immature CD4SP subset, suggesting that medullary APCs may facilitate maturation of thymocyte after positive selection for efficient induction of Foxp3. In summary, this study suggest that Treg cell development is driven by self-antigen encounter of CD4SP cells, and TCR reactivity for self-antigen plays an instructive role in Treg cell differentiation, thereby ii thymic tolerance mechanisms prevent autoimmunity by restraining the escape of selfreactive effector T cells into the periphery. iii