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Loss of IRF-4–binding protein leads to the spontaneous development of systemic autoimmunity
Jessica C. Fanzo, … , Steven Greenberg, Alessandra B. Pernis
Jessica C. Fanzo, … , Steven Greenberg, Alessandra B. Pernis
Published March 1, 2006
Citation Information: J Clin Invest. 2006;116(3):703-714. https://doi.org/10.1172/JCI24096.
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Research Article Immunology

Loss of IRF-4–binding protein leads to the spontaneous development of systemic autoimmunity

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Abstract

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.

Authors

Jessica C. Fanzo, Wen Yang, So Young Jang, Sanjay Gupta, Qinzhong Chen, Ayesha Siddiq, Steven Greenberg, Alessandra B. Pernis

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Figure 5

IBP regulates T cell effector function.

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IBP regulates T cell effector function.
(A) IL-2 production by WT and IB...
(A) IL-2 production by WT and IBP mutant T cells. Purified CD4+ T cells were stimulated with immobilized anti-CD3ε antibody (1 μg/ml) alone or together with soluble anti-CD28 antibody (1 μg/ml) (left panel) or with PMA (50 ng/ml) and ionomycin (1 μM) (right panel) for 24 hours. IL-2 levels in culture supernatants were determined by ELISA. The experiment is representative of 5 independent experiments. (B) IFN-γ and IL-4 production by WT and IBP mutant T cells. Cells were stimulated as in A for 48 hours. Production of IFN-γ (left panel) and IL-4 (right panel) was measured by ELISA. The experiment is representative of 5 independent experiments. (C) In vitro differentiation of IBP+/+ and IBPtrap/trap naive Th cells. Naive CD4+ T cells were isolated from WT and IBPtrap/trap mice and differentiated in vitro under unskewed, Th1, or Th2 conditions. After 7 days, unskewed, Th1, and Th2 cells from IBP+/+ and IBPtrap/trap mice were stimulated with anti-CD3 antibody for 24 hours and supernatants analyzed for cytokine production. IFN-γ (left panel) and IL-4 (right panel) production was measured by ELISA. The experiment is representative of 5 independent experiments.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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