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Glucocorticoid-induced TNFR (GITR) has been implicated as an essential regulator of immune responses to self tissues and pathogens. We have recently shown that GITR-induced cellular events promote survival of naive T cells, but are insufficient to protect against activation-induced cell death. However, the molecular mechanisms of GITR-induced signal transduction that influence physiologic and pathologic immune responses are not well understood. TNFR-associated factors (TRAFs) are pivotal adapter proteins involved in signal transduction pathways of TNFR-related proteins. Yeast two-hybrid assays and studies in HEK293 cells and primary lymphocytes indicated interactions between TRAF2 and GITR mediated by acidic residues in the cytoplasmic domain of the receptor. GITR-induced activation of NF-kappaB is blocked by A20, an NF-kappaB-inducible protein that interacts with TRAFs and functions in a negative feedback mechanism downstream of other TNFRs. Interestingly, in contrast with its effects on signaling triggered by other TNFRs, our functional studies revealed that TRAF2 plays a novel inhibitory role in GITR-triggered NF-kappaB activation.

Glucocorticoid-induced TNFR (GITR) is a member of the TNFR family that can inhibit the suppressive function of regulatory T cells and promote the survival and activation of T cells. However, little is known about the molecular mechanisms regulating T cell survival and activation downstream of GITR. To gain further insight into the cellular events and signaling pathways triggered by GITR, survival, proliferation, and cytokine production as well as activation of MAPKs and NF-kappaB were monitored after cross-linking of the receptor on naive and activated T cells. GITR cross-linking provided costimulation of naive and activated T cells and resulted in activation of MAPKs and NF-kappaB. Although GITR-induced signaling pathways augmented the survival of naive T cells, they were not sufficient to inhibit activation-induced cell death triggered by CD3 cross-linking of activated T cells. Differences in the contributions of GITR to cell survival between naive and activated T cells suggest that the receptor triggers specific pathways depending on the activation state of the T cell.

Effector cells play a crucial role in the immune system of higher vertebrates in eliminating invading pathogens and transformed cells that could cause disease or death of the individual. To be effective and specific, immune responses have to distinguish between self and nonself. Mechanisms of central and peripheral tolerance have evolved to control effector cells that could respond to autoantigens. Regulatory T-cells (Treg cells) are critical modulators of effector cells in the periphery that suppress autoreactive T-cells but are also involved in modulating immune responses against invading pathogens. Identification of surface markers of Treg cells and the development of in vitro systems to study the suppressive function of Treg cells have revealed distinct phenotypic and functional subsets of Treg cells. Several tumor necrosis factor receptor (TNFR) family members have been shown to play a role in the development, homeostasis, and suppressor function of Treg cells. Recent findings suggest that TNFRs and other cell-surface molecules of Treg cells can be explored for therapeutic strategies targeting autoimmune disorders, cancer, and immune responses against pathogens.

Members of the TNF receptor (TNFR) superfamily are cell-surface proteins that can be found on most cell types including lymphocytes. Although some TNFR-related molecules are constitutively expressed, others, such as CD30 and Ox40, are induced upon activation of lymphocytes. CD30 and Ox40 are predominantly expressed on activated T helper (T(h))2 cells. Both receptors can activate c-Jun N-terminal kinase (JNK) and nuclear factor-kappaB (NF-kappaB) and have been suggested to play costimulatory roles in lymphocyte activation. To gain further insight into events triggered by both TNFR-related molecules, a detailed analysis of their expression patterns has been performed. We found that CD30 and Ox40 were coexpressed on T(h)2 cells. However, in contrast to CD30, Ox40 was also expressed on T(h)1 cells. Although expression of both receptors is augmented by interleukin-4, only CD30 expression is dependent on signal transducer and activator of transcription (STAT)-6-mediated signaling. Differences in the regulatory pathways controlling expression of CD30 and Ox40 suggest distinct, functional effects triggered by the two TNFR-related molecules during lymphocyte activation.