Effective immune responses require the appropriate activation and differentiation of peripheral CD4+ T cells. These processes need to be followed by the timely elimination of the responding T cells in order to restore T cell homeostasis. Defects in the appropriate regulation of T cell activation, expansion, and survival underlie the pathogenesis of many autoimmune disorders. The molecular machinery employed by T cells to properly control these processes and prevent the onset of autoimmunity has not been fully elucidated. This proposal focuses on a novel protein termed IBP. IBP exhibits significant homology to SWAP-70, a novel type of activator for Rho GTPases. IBP is the only member of this novel family of proteins expressed in T cells. Our laboratory has previously shown that, upon TCR engagement, IBP is recruited to the immunological synapse and activates Rho GTPases. Interestingly, mice deficient in IBP develop, with age, a lupus-like syndrome. We have recently generated TCR transgenic (DO11.10) IBP deficient mice. These mice rapidly develop autoimmune arthritis and vasculitis. The pathophysiology observed in the absence of IBP is not associated with impairments in central tolerance but is instead accompanied by three major abnormalities within the peripheral CD4+ T cell compartment: hyperresponsiveness to low-levels of stimulation, inappropriate acquisition of TH effector functions, and impaired elimination of activated T cells. Taken all together, these findings have led us to hypothesize that IBP is a novel regulator of T cell activation and homeostasis that is critical for the prevention of autoimmune pathophysiology. The overall goal of this proposal is to gain a mechanistic understanding of the role of IBP in T cell function and homeostasis. Specifically, we will: 1) Dissect the mechanisms by which IBP regulates the ability of CD4+ T cells to discriminate the potency of TCR ligation, 2) Investigate the pathways employed by IBP to control T cell effector function, and 3) Ascertain the mechanisms used by IBP to regulate T cell survival. Relevance: This proposal focuses on dissecting the role of a novel molecule, IBP, in autoimmunity. Lack of IBP in mice leads to the spontaneous development of autoimmunity. This proposal will shed novel insights into the molecular networks responsible for the maintenance of T cell tolerance. This knowledge will be critical for the development of novel strategies aimed at targeting autoimmune diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Noel, Patricia
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Hospital for Special Surgery
New York
United States
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Stirzaker, R A; Biswas, P S; Gupta, S et al. (2012) Administration of fasudil, a ROCK inhibitor, attenuates disease in lupus-prone NZB/W F1 female mice. Lupus 21:656-61
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Biswas, Partha S; Bhagat, Govind; Pernis, Alessandra B (2010) IRF4 and its regulators: evolving insights into the pathogenesis of inflammatory arthritis? Immunol Rev 233:79-96
Biswas, Partha S; Gupta, Sanjay; Chang, Emily et al. (2010) Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice. J Clin Invest 120:3280-95
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Chen, Qinzhong; Gupta, Sanjay; Pernis, Alessandra B (2009) Regulation of TLR4-mediated signaling by IBP/Def6, a novel activator of Rho GTPases. J Leukoc Biol 85:539-43
Pernis, A B (2009) Th17 cells in rheumatoid arthritis and systemic lupus erythematosus. J Intern Med 265:644-52
Chen, Qinzhong; Yang, Wen; Gupta, Sanjay et al. (2008) IRF-4-binding protein inhibits interleukin-17 and interleukin-21 production by controlling the activity of IRF-4 transcription factor. Immunity 29:899-911

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