The thymus and central tolerance

Abstract

T–cell differentiation in the thymus generates a peripheral repertoire of mature T cells that mounts strong responses to foreign antigens but is largely unresponsive to self–antigens. This state of specific immunological tolerance to self–components involves both central and peripheral mechanisms. Here we review the process whereby many T cells with potential reactivity for self–antigens are eliminated in the thymus during early T–cell differentiation. This process of central tolerance (negative selection) reflects apoptosis and is a consequence of immature T cells receiving strong intracellular signalling through T–cell receptor (TCR) recognition of peptides bound to major 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 cells (APCs); whether tolerance also occurs in the cortex is still controversial. Tolerance induction requires a combination of TCR ligation and co–stimulatory signals. Co–stimulation reflects interaction between complementary molecules on T cells and APCs and probably involves multiple molecules acting 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 include tissue–specific antigens; central tolerance to these latter antigens, however, is likely to be limited to high–affinity T cells, leaving low–affinity cells to escape. Tolerance to alloantigens and the possibility of using central tolerance to promote acceptance of allografts are discussed.