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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 3

Accumulation of effector/memory-like T cells and terminally differentiated B cells in aging IBPtrap/trap mice.

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Accumulation of effector/memory-like T cells and terminally differentiat...
(A) Increased effector/memory T cells in aging IBPtrap/trap female mice. Cell suspensions from spleen (top panels), and lymph nodes (bottom panels) from older IBP+/+ and IBPtrap/trap mice were stained with antibodies against CD4, CD44, and CD62L to evaluate the presence of naive (CD44loCD62Lhi) and effector/memory (CD44hiCD62Llo) T cells. Dot plots represent gated CD4+ populations. Percentages of positive cells within each gate are shown. Results are representative of 5 different mice. (B) Alterations of B cell populations in aging IBPtrap/trap female mice. Single-cell suspensions from spleen (top panels) and lymph nodes (bottom panels) from aging IBP+/+ and IBPtrap/trap female mice were stained with antibodies against B220, IgM, and IgD. Cell staining was analyzed by FACS. Dot plots represent gated B220+ populations. Percentages of positive cells within each gate are shown. (C) Increased plasma cells in spleens of aging IBPtrap/trap female mice. Single-cell suspensions from spleen (top panels) and bone marrow (bottom panels) from IBP+/+ and older IBPtrap/trap female mice were stained with antibodies against B220 and syndecan-1. Cell staining was analyzed by FACS. Percentages of syndecan-1–positive cells within each gate are shown. (D) Syndecan-1 and PNA staining of spleens of aging IBPtrap/trap female mice. Anti–syndecan-1 (blue) and anti-PNA (red) staining were performed on spleens from IBP+/+ (left panel) and IBPtrap/trap (right panel) mice. Light microscopy magnification, ×10. (E) Accumulation of IgG1+ cells in spleens of aging IBPtrap/trap female mice. Anti-IgG1 (blue) staining was performed on spleens from IBP+/+ (left panel) and IBPtrap/trap (right panel) mice. Light microscopy magnification, ×10.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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