Signaling triggered by glucocorticoid-induced tumor necrosis factor receptor family-related gene: regulation at the interface between regulatory T cells and immune effector cells.
Mammals and other higher vertebrates have developed an adaptive immune system to defy effectively countless pathogens and cancerous cells encountered during the lifetime of an individual. B and T lymphocytes, which are essential in orchestrating adaptive immune responses, express surface receptors specific for foreign and abnormal self-antigens. Genesis of this antigen receptor repertoire poses significant risks for autoimmunity caused by self-reactive lymphocytes. Therefore, organisms with adaptive immune systems have evolved central and peripheral tolerance mechanisms. In peripheral tissues, regulatory T (Treg) cells function in a dominant, cell-extrinsic manner to limit inflammatory responses and autoimmune disorders. To tap the potential clinical utility of these specialized lymphocytes, advances have been made in understanding how Treg cell-mediated suppression of immune effector cells is achieved and regulated. Importantly, signaling induced by a recently identified member of the tumor necrosis factor receptor (TNFR) family, termed glucocorticoid-induced TNFR family-related gene (GITR), abrogates the suppressive effects of Treg cells. GITR plays a pivotal role in controlling T cell-mediated responses in experimental models of organ-specific autoimmunity, chronic infection, and anti-tumor immunity. These findings highlight the importance of elucidating the molecular underpinnings of GITR-induced signaling. We propose that GITR employs adapter proteins, including TNFR-associated factors (TRAFs), to regulate diverse signaling pathways and transcriptional programs that control the interplay between Treg cells and immune effector cells.
Esparza
Edward M
EM
Department of Medicine, Washington University, School of Medicine, Saint Louis, MO 63110, USA.
Arch
Robert H
RH
D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D001327:Autoimmune Diseases / Q000276:immunology; D001402:B-Lymphocytes / Q000378:metabolism; D060908:CTLA-4 Antigen; D051858:Forkhead Transcription Factors / Q000378:metabolism; D053450:Glucocorticoid-Induced TNFR-Related Protein; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D007107:Immune System; D007249:Inflammation; D007376:Interleukin-2 / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053450:Glucocorticoid-Induced TNFR-Related Protein; D005938:Glucocorticoids; D007376:Interleukin-2; D016328:NF-kappa B; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C491405:TNFRSF18 protein, human; D014409:Tumor Necrosis Factor-alpha