Figure 1. Central and peripheral immunological tolerance.

Although T cells originate from the fetal liver and adult bone marrow, the thymus is the major site of T cell maturation. The selection of developing T cells is dependent on T cell receptor (TCR) recognition of self-peptide-major histocompatibility complex (self-peptide-MHC) molecules and results in the elimination of potentially harmful T cell clones. Positive selection is a process mediated by cortical thymic epithelial cells (cTEC) during which immature thymocytes whose TCRs fail to recognize self-peptide-MHC undergo a default pathway of apoptosis; a phenomenon known as “death by neglect”. Thymocytes whose TCRs recognize peptide-MHC presented by medullary thymic epithelial cells (mTEC) with high avidity undergo a process of negative selection resulting in apoptosis. In an alternative process that is incompletely understood, thymocytes bearing TCRs with intermediate avidities towards self-peptide-MHC are selected onto the Treg cell lineage via at least two distinct progenitor subsets including a CD25⁺Foxp3⁻ and CD25⁻ Foxp3^low regulatory T cell population. The elimination of potentially harmful self-reactive T cells in the thymus through negative selection is the basis for0 central tolerance. In contrast, peripheral tolerance is induced in mature lymphocytes by self-antigens, including components of the extended self and innocuous environmental antigens by a pool of regulatory T cells derived from the thymus (nTreg) or generated in the periphery (pTreg) that act in concert to maintain organismal-wide immunological tolerance.