Apoptotic signal transduction and T cell tolerance.
ABSTRACT The healthy immune system makes use of a variety of surveillance mechanisms at different stages of lymphoid development to prevent the occurrence and expansion of potentially harmful autoreactive T cell clones. Disruption of these mechanisms may lead to inappropriate activation of T cells and the development of autoimmune and lymphoproliferative diseases [such as multiple sclerosis, rheumatoid arthritis, lupus erythematosus, diabetes and autoimmune lymphoproliferative syndrome (ALPS)]. Clonal deletion of T cells with high affinities for self-peptide-MHC via programmed cell death (apoptosis) is an essential mechanism leading to self-tolerance. Referred to as negative selection, central tolerance in the thymus serves as the first checkpoint for the developing T cell repertoire and involves the apoptotic elimination of potentially autoreactive T cells clones bearing high affinity T cell receptors (TCR) that recognize autoantigens presented by thymic epithelial cells. Autoreactive T cells that escape negative selection are held in check in the periphery by either functional inactivation ("anergy") or extrathymic clonal deletion, both of which are dependent on the strength and frequency of the TCR signal and the costimulatory context, or by regulatory T cells. This review provides an overview of the different molecular executioners of cell death programs that are vital to intrathymic or extrathymic clonal deletion of T cells. Further, the potential involvement of various apoptotic signaling paradigms are discussed with respect to the genesis and pathophysiology of autoimmune disease.
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ABSTRACT: Most developing thymocytes undergo apoptosis because they cannot interact productively with molecules encoded by the major histocompatibility complex. Here, we show that mice lacking the orphan nuclear hormone receptor RORγ lose thymic expression of the anti-apoptotic factor Bcl-xL. RORγ thus regulates the survival of CD4+8+ thymocytes and may control the temporal window during which thymocytes can undergo positive selection. RORγ was also required for development of lymph nodes and Peyer's patches, but not splenic follicles. In its absence, there was loss of a population of CD3–CD4+CD45+ cells that normally express RORγ and that are likely early progenitors of lymphoid organs. Hence, RORγ has critical functions in T cell repertoire selection and lymphoid organogenesis.Science 06/2000; 288(5475):2369-2373. · 31.20 Impact Factor
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ABSTRACT: Two principal pathways for apoptosis initiation exist. One pathway, which is also termed the 'extrinsic' pathway, is mediated by death receptors, a subgroup of the TNF receptor superfamily. The second pathway, which is also referred to as the 'intrinsic' pathway is controlled by members of the Bcl-2 family. A long standing discussion revolves around the question of how these two pathways influence each other in regulating the decision about life or death of a cell. Here, we review our current knowledge about the interactions between these two pathways and discuss current models which could help to resolve previous apparently contradictory results.Biochimica et Biophysica Acta 04/2004; 1644(2-3):125-32. · 4.66 Impact Factor
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ABSTRACT: TRAIL, the tumor necrosis factor-related apoptosis-inducing ligand, selectively induces apoptosis of tumor cells, but not most normal cells. Its role in normal, nontransformed tissues is not clear. We report here that mice deficient in TRAIL have a severe defect in thymocyte apoptosis-thus, thymic deletion induced by T cell receptor ligation is severely impaired. TRAIL-deficient mice are also hypersensitive to collagen-induced arthritis and streptozotocin-induced diabetes and develop heightened autoimmune responses. Thus, TRAIL mediates thymocyte apoptosis and is important in the induction of autoimmune diseases.Nature Immunology 04/2003; 4(3):255-60. · 26.20 Impact Factor