Interleukin-2-Inducible T-cell Kinase (ITK) signaling regulates non-canonical regulatory T cells

Abstract

Abstract Regulatory T cells (Tregs) play an indispensable role in maintaining immunological tolerance to self-antigens and foreign antigens in suppressing excessive immune responses deleterious to the host by exerting a suppressive program towards a wide variety of target immune cells. Here we showed that ITK signaling pathways control the increased frequency of “Non-Canonical” CD4+CD25−FoxP3+ Tregs (ncTregs) population as well as canonical Tregs CD4+CD25+FoxP3+ expression significantly. Using several animals models we demonstrated that transplanting ncTregs and cTregs from ITK deficient mice ameliorated WT T cells mediated Graft versus Host Disease (GVHD). Furthermore, our data showed that adaptively transferring ncTregs and cTregs from ITK deficient mice significantly reduces proinflammatory cytokine production and T cell proliferation in GVHD induced recipient mice. Furthermore, our data uncover that adaptatively transferring ncTregs and cTregs from ITK deficient mice to GVHD induced recipient mice reduced tissue damage which induced by WT T cells. Finally, we have recently developed a novel peptide inhibitor which enhance Tregs expression in both mice and human. This novel peptide inhibitor also reduced cytokine production in mice and primary GVHD patient samples. Our data demonstrated that targeting specifically SLP76:ITK signaling could be used as a therapeutic strategy not only limit to GVHD but also treat multiple T cells mediated autoimmune disorders.