Act1 modulates autoimmunity through its dual functions in CD40L/BAFF and IL-17 signaling.
Coordinated regulation of T and B cell-mediated immune responses plays a critical role in the control and modulation of autoimmune diseases. This review is focused on the adapter molecule Act1 and its regulation of autoimmunity through its impact on both T and B cell-mediated immune responses. Whereas Act1 molecule is an important negative regulator for B cell-mediated humoral immune responses through its function in CD40L and BAFF signaling, recent studies have shown that Act1 is also a key positive signaling component for IL-17 signaling pathway, critical for T(H)17-mediated autoimmune and inflammatory responses. The dual functions of Act1 are evident in Act1-deficient mice that displayed B cell-mediated autoimmune phenotypes (including dramatic increase in peripheral B cells, lymphadenopathy and splenomegaly, hypergammaglobulinemia and Sjogren's disease in association with Lupus Nephritis), but showed resistance to T(H)17-dependent EAE and colitis. Such seemingly opposite functions of Act1 in CD40-BAFFR and IL-17R signaling are orchestrated by different domains in Act1. Whereas Act1 interacts with the IL-17R through the C-terminal SEFIR domain, Act1 is recruited to CD40 and BAFFR indirectly, which is mediated by TRAF3 through the TRAF binding site in Act1. Such delicate regulatory mechanisms may provide a common vehicle to promote balance between host defense to pathogens and tolerance to self.
Department of Immunology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. lix@ccf.org
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Li
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000917:Antibody Formation / Q000502:physiology; D015551:Autoimmunity / Q000502:physiology*; D053264:B-Cell Activating Factor / Q000502:physiology*; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D019013:CD40 Antigens; D023201:CD40 Ligand / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000503:physiopathology; D020381:Interleukin-17 / Q000502:physiology; D008954:Models, Biological; D016328:NF-kappa B / Q000502:physiology; D017472:Receptors, Interleukin-1 / Q000502:physiology; D053722:Receptors, Interleukin-17 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D051193:Toll-Like Receptors / Q000502:physiology; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D019013:CD40 Antigens; D020381:Interleukin-17; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D053722:Receptors, Interleukin-17; C414202:TRAF3IP2 protein, human; D051193:Toll-Like Receptors; C515963:Traf3ip2 protein, mouse; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D023201:CD40 Ligand; D051550:I-kappa B Kinase