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duties requires careful discrimination between self and non-self, a distinction whose borders are constantly reassessed throughout the lifetime of the cell. Of clear importance to T cell function is the nature of the T cell receptor for antigen (TCR), a heterodimeric cell surface molecule monoclonally expressed by each individual T cell. This TCR recognizes short peptide antigens bound to a groove within molecules encoded by the major histocompatibility complex (MHC) or to longer gly-coproteins called superantigens, presented outside the peptide binding groove of the MHC.1,2 One of the first challenges facing developing T cells within the thymus, the organ in which T cells mature, is the assembly of diverse TCRs through recombination of the separate gene elements that together encode this protein.3 TCR-a and -b gene rearrangement occurs by a developmentally-regulated process mediated by the products of recombination activating gene (RAG)1 and RAG2.4 The TCR repertoire is selected within the thymus for recognition of the multitude of peptide antigens presented by self MHC molecules and culled of overt self reactivity.5 This latter intrathymic process, termed negative selection, requires that thymocytes be exposed to the relevant self antigens.6 Although intrathymic expression of antigens once believed to be strictly tissue-specific has recently expanded the pool of known contributors to negative selection, 7 alternate forms of tolerance induction must exist to handle mature peripheral T cells recognizing age-dependent or tissue-specific antigens.

Although intrathymic negative selection operates primarily to eliminate overtly self-reactive thymocytes through programmed cell death, the induction of tolerance among mature peripheral T cells has been shown to operate through many pathways.8 Autoreactive T cells may be prevented from encountering antigen in a context that could lead to cell activation.9 On the other hand, these T cells may meet antigen and be rendered anergic (nonfunctional) to further stimulation through their TCRs.10 Anergic T cells generally have a shortened lifespan and may appear phenotypically normal or may express reduced surface levels of TCR and/ or CD4 or CD8 coreceptor molecules. Self reactive cells may be directly eliminated without traversing an anergic state, or may be driven into terminal differen

Figure E2.1. Schematic diagram of the alternate pathways to tolerance for mature CD4+ T cells in Vp5 Tg Mtv-8+ mice. Vp5+CD4+ T cells that encounter Mtv-8 in the lymphoid periphery either become anergic and die, or revise their TCRs, thereby eliminating Mtv-8 reactivity. T cells that undergo TCR revision express a diverse repertoire and contribute to the self-tolerant, functional T cell pool.

Figure E2.1. Schematic diagram of the alternate pathways to tolerance for mature CD4+ T cells in Vp5 Tg Mtv-8+ mice. Vp5+CD4+ T cells that encounter Mtv-8 in the lymphoid periphery either become anergic and die, or revise their TCRs, thereby eliminating Mtv-8 reactivity. T cells that undergo TCR revision express a diverse repertoire and contribute to the self-tolerant, functional T cell pool.

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