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

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 8

T cells display impaired synapse formation and actin polymerization.

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IBPtrap/trap T cells display impaired synapse formation and actin polyme...
(A) Formation of the immunological synapse in IBPtrap/trap CD4+ T cells. CD4+ T cells were conjugated with A20 mouse B lymphoma cells loaded with or without 2 μg/ml SEE. After the indicated times of T and B cell contact, cells were stained with antibodies against either phosphorylated ZAP-70 or phosphorylated LAT and scored under a fluorescence microscope. Approximately 50 conjugates were counted per time point in at least 3 independent experiments. T and B cell conjugates without SEE (upper panels) and with SEE (lower panels) are shown. (B) Representative images for conjugates (phase), phosphorylated ZAP-70 (red) and CD4 (green) at 5 minutes in IBP+/+ and IBPtrap/trap T cells, respectively. (C) Actin polymerization in IBPtrap/trap CD4+ T cells reconstituted with WT or mutant IBP retroviral vectors. Naive CD4+ T cells were infected with control YFP-RV (empty vector) and WT IBP–expressing (IBP-RV), IBP-Δ313-631–expressing (IBP-Δ313-631-RV), or constitutively active Rac2–expressing (CA Rac2-RV) retroviruses. Cells were harvested after 5 days and restimulated with anti-CD3ε antibodies followed by cross-linking with goat anti-hamster Ig at 4°C (control) or 37°C. Cells were then stained with biotin-labeled phalloidin followed by streptavidin-PE (PE-phalloidin) and actin polymerization measured by FACS. Data shown represent unstimulated cells (filled histogram) with overlay of stimulated cells (open histogram) after gating on YFP-positive cells.