Signaling by the TNF Receptor Minireview Superfamily and T Cell Homeostasis

across the family. Biological responses mediated by TNF␣ range from gene induction events that mediate inflammatory responses to cellular apoptosis and necro-which may limit their ability to activate lymphocytes (Wang et al., 1999). TNF␣ binds to two distinct, type I membrane receptors One of the hallmarks of the immune system is the con-on the cell surface, TNFR-1 (p55/p60) and TNFR-2 (p75/ stant expansion and contraction of different cell popula-p80), while Fas-L binds to another TNFR-like molecule tions as a result of homeostatic immune regulation. called Fas/CD95/Apo-1. The extracellular domains Expansion and proliferation of T and B lymphocytes and (ECDs) of the TNFRs contain one to six characteristic antigen-presenting cells (APCs) in the midst of antigenic cysteine-rich domains (CRDs). They can be further di-challenges is countered by contraction of the same pop-vided into two subgroups based on the structure of ulations of cells through apoptosis as the immune reac-their cytoplasmic tails. TNFR-1 and Fas/CD95/Apo-1 are tion attenuates. Hence, apoptosis or programmed cell representatives of a subset of TNFR-like receptors that death is at the heart of homeostatic balance within the share a homologous motif in the cytoplasmic tail called immune system. Members of the tumor necrosis factor the " death domain " (DD). Upon activation, the DD serves (TNF) receptor superfamily play critical roles in lympho-as a docking site for DD-containing adaptor proteins cyte apoptosis during immune regulation. We will focus such as TRADD (for TNFR-1) and FADD (for Fas) through our discussion on how structural features of TNF recep-homotypic DD interactions. Ultimately, the recruitment tor (TNFR)-like receptors affect the regulation of T cell of caspase-8 or-10 via FADD initiates the enzymatic homeostasis. cascade of apoptosis. Consistently, FADD or caspase-8 deficiencies lead to resistance of apoptosis induction by Fas and TNFR-1. For the TNFR-1 signaling complex, Apoptosis in Central and Peripheral Tolerance In the thymus, the developing T cell repertoire under-receptor activation can also lead to the recruitment of RIP and TRAF2 through TRADD (Figure 1B). RIP is a goes positive and negative selection to achieve effectiveness against foreign antigenic challenge and to DD-containing kinase that is crucial for NF-␬B activation while TRAF2 activates the MAP kinases. Both RIP or minimize the possibility of reaction to self-antigens. Evidence indicates that most thymocytes do not employ TRAF2 deficiencies result in hypersensitivity to TNF␣-induced cytotoxicity (reviewed in Wallach et al., 1999). TNFR-like receptors in death induction. Mature T cells are subject to further …