[Show abstract][Hide abstract] ABSTRACT: TLRs play a fundamental role in innate immune responses. Although Rho GTPases have been implicated in TLR-mediated signaling pathways, the molecules that control their activation in response to TLR engagement are largely unknown. IFN regulatory factor-4-binding protein (IBP; which is encoded by the gene Def6) is a unique type of activator for Rac that plays a crucial role in TCR-mediated signaling and adaptive immune responses. Here, we demonstrate that IBP/Def6 also controls innate immune responses by modulating TLR-induced signaling events. Mice deficient in IBP/Def6 are protected from LPS-induced septic shock. This protection is associated with a decrease in the production of proinflammatory cytokines and is accompanied by diminished activation of MAPKs and NF-kappaB. Our results thus identify IBP/Def6 as a novel component of the TLR4-induced signaling cascade that controls the production of proinflammatory cytokines.
[Show abstract][Hide abstract] ABSTRACT: The T helper 17 (Th17) cell lineage is important in inflammatory and autoimmune responses, via its ability to produce interleukin-17 (IL-17) and IL-21. Given the potentially deleterious effects of Th17 cells, their generation needs to be strictly controlled. IRF-4 is a transcription factor that has recently emerged as a key regulator of Th17 cell differentiation. Here, we showed that mice deficient in a previously isolated protein, IBP (IRF-4-binding protein), rapidly developed rheumatoid arthritis-like joint disease and large-vessel vasculitis. The pathology was associated with an enhanced responsiveness of T cells to low levels of stimulation and with the inappropriate synthesis of IL-17 and IL-21. IBP sequestered IRF-4 and prevented it from targeting the transcriptional regulatory regions of the genes that encode IL-17 and IL-21. Thus, IBP appears to be important in preventing T cell-mediated autoimmunity by ensuring that the production of IL-17 and IL-21 does not occur in response to self-antigens.
[Show abstract][Hide abstract] 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.