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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL062215-08
Application #
7810700
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Noel, Patricia
Project Start
2001-05-15
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
8
Fiscal Year
2010
Total Cost
$394,125
Indirect Cost
Name
Hospital for Special Surgery
Department
Type
DUNS #
622146454
City
New York
State
NY
Country
United States
Zip Code
10021
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
Biswas, Partha S; Gupta, Sanjay; Stirzaker, Roslynn A et al. (2012) Dual regulation of IRF4 function in T and B cells is required for the coordination of T-B cell interactions and the prevention of autoimmunity. J Exp Med 209:581-96
Biswas, Partha S; Kang, Kyuho; Gupta, Sanjay et al. (2012) A murine autoimmune model of rheumatoid arthritis and systemic lupus erythematosus associated with deregulated production of IL-17 and IL-21. Methods Mol Biol 900:233-51
Biswas, Partha S; Gupta, Sanjay; Chang, Emily et al. (2011) Aberrant ROCK activation promotes the development of type I diabetes in NOD mice. Cell Immunol 266:111-5
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
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, Alessandra B (2009) Rho GTPase-mediated pathways in mature CD4+ T cells. Autoimmun Rev 8:199-203
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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