Icos-Dependent Pi3k Signaling In Regulatory T Cell Development And Function

Abstract Foxp3+ regulatory T cells (TR) are critical for maintaining immune tolerance and preventing inflammatory disease. Given their immunosuppressive capabilities, manipulation of TR function and/or abundance is a promising therapeutic strategy to either augment or inhibit immune responses in the context of disease. A detailed understanding of the key factors that control TR development, homeostasis, and function is essential for the successful application of TR-based therapies. Recent work suggests that inducible T cell costimulator (ICOS) signaling is required for maintenance of effector TR (eTR) cells, which migrate to peripheral sites of inflammation. ICOS ligation is most notably a potent activator of phosphatidylinositol 3-kinase (PI3K), however the key signaling pathways downstream of ICOS that support eTR have not been investigated. In order to study the role of ICOS-dependent PI3K signaling, we obtained mice that carry a knock-in mutation in the Icos gene that alters the cytoplasmic tail motif of the ICOS protein, thereby specifically abolishing ICOS-mediated PI3K activation (IcosY181F mice). The frequency of TR is reduced in these mice, as is the proliferation of ICOShi TR in secondary lymphoid organs. CD4+ IcosY181F cells have impaired regulation of downstream PI3K targets, including p-AKT, p-S6, and CD62L. IcosY181F mice develop more severe disease earlier than WT controls using a model of experimental autoimmune encephalomyelitis and have lower eTR frequencies at effector sites. Taken together, data from our lab suggest an important role for ICOS-mediated PI3K activation in the development, maintenance, and function of TR.