Glucocorticoid-induced TNF receptor, a costimulatory receptor on naive and activated T cells, uses TNF receptor-associated factor 2 in a novel fashion as an inhibitor of NF-kappa B activation.

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.
Mesh Terms:
Amino Acid Sequence, Animals, Carrier Proteins, Cell Line, Conserved Sequence, Cysteine Endopeptidases, Cytoplasm, Down-Regulation, G0 Phase, Glucocorticoid-Induced TNFR-Related Protein, Humans, Hydrogen-Ion Concentration, Intracellular Signaling Peptides and Proteins, Lymphocyte Activation, Mice, Mice, Transgenic, Molecular Sequence Data, NF-kappa B, Nuclear Proteins, Protein Structure, Tertiary, Protein Transport, Proteins, Receptors, Nerve Growth Factor, Receptors, Tumor Necrosis Factor, TNF Receptor-Associated Factor 2, Transfection, Tumor Necrosis Factors
J. Immunol.
Date: Jun. 15, 2005
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