The thymus and central tolerance

T-cell differentiation in the thymus generates a peripheral repertoire of m ature Tcells that mounts strong responses to foreign antigens but is largel y unresponsive to self-antigens. This state of specific immunological toler ance to self-components involves both central and peripheral mechanisms. He re we review the process whereby many Tcells with potential reactivity for self-antigens are eliminated in the thymus during early T-cell differentiat ion. This process of central tolerance (negative selection) reflects apopto sis and is a consequence of immature Tcells receiving strong intracellular signalling through T-cell receptor (TCR) recognition of peptides bound to m ajor histocompatibility complex: (MHC) molecules. Central tolerance occurs mainly in the medullary region of the thymus and depends upon contact with peptide MHC complexes expressed on bone-marrow-derived antigen-presenting c ells (APCs!; whether tolerance also occurs in the cortex is still controver sial. Tolerance induction requires a combination of TCR ligation and co-sti mulatory signals. Co-stimulation reflects interaction between complementary molecules on Tcells and APC's and probably involves multiple molecules act ing in consort, which may account for why deletion of individual molecules with known or potential co-stimulatory function has little or no effect on central tolerance. The range of self-antigens that induce central tolerance is considerable and, via low level expression in the thymus, may also incl ude tissue-specific antigens; central tolerance to these latter antigens, h owever, is likely to be limited to high-affinity T cells, leaving low-affin ity) cells to escape. Tolerance to alloantigens and the possibility of usin g central tolerance to promote acceptance of allografts are discussed.