Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 116, Issue 3, Pages 703-714Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI24096
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Funding
- NHLBI NIH HHS [R01 HL-62215, R01 HL062215] Funding Source: Medline
- NIAID NIH HHS [T32-AI07525, P01 AI050514, T32 AI007525, P01 AI50514-01] Funding Source: Medline
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IFN regulatory factor 4-binding (IRF-4-binding) protein (IBP) is a novel type of activator of Rho GTPases that is recruited to the immunological synapse upon TCR stimulation. Here we demonstrate that loss of IBP leads to the spontaneous development of a systemic autoimmune disorder characterized by the accumulation of effector/memory T cells and IgG(+) B cells, profound hypergammaglobulinemia, and autoantibody production. Similar to human SLE, this syndrome primarily affects females. T cells from IBP-deficient mice are resistant to death in vitro as well as in vivo and exhibit selective defects in effector function. In the absence of IBP, T cells respond suboptimally to TCR engagement, as demonstrated by diminished ERK1/2 activation, decreased c-Fos induction, impaired immunological synapse formation, and defective actin polymerization. Transduction of IBP-deficient T cells with a WT IBP protein, but not with an IBP mutant lacking the Dbl-like domain required for Rho GTPase activation, rescues the cytoskeletal defects exhibited by these cells. Collectively, these findings indicate that IBP, a novel regulator of Rho GTPases, is required for optimal T cell effector function, lymphocyte homeostasis, and the prevention of systemic autoimmunity.
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