SLAT/Def6 Plays a Critical Role in the Development of Th17 Cell-Mediated Experimental Autoimmune Encephalomyelitis

SWAP-70-like adapter of T cells (SLAT; also known as Def6) is a novel guanine nucleotide exchange factor for Rho GTPases that has been previously shown to play a role in CD4 ؉ T cell activation and Th1/Th2 differentiation. However, the role of SLAT/Def6 in autoimmunity and its associated Th1-and Th17-specific responses has not yet been clearly elucidated. We used a prototypical and pathologically relevant Th1/Th17-mediated autoimmune model, that is, experimental autoimmune encephalomyelitis, to assess the role of SLAT/Def6 in autoantigen-specific T cell response. We found that T cell-expressed SLAT/Def6 was critical for experimental autoimmune encephalomyelitis development and pathogenesis, as evidenced by the resistance of Def6-deficient (Def6 ؊/؊) mice to clinical signs of the disease associated with a lack of CNS inflammation and demyelination in myelin oligodendrocyte glycoprotein-immunized Def6 ؊/؊ mice. Moreover, Def6 deficiency resulted in a severely diminished myelin oligodendrocyte gly-coprotein-specific CD4 ؉ T cell proliferation as well as a defect in IFN-␥ and IL-17 production in secondary lymphoid organs and the CNS. Lastly, Def6 ؊/؊ CD4 ؉ T cells were grossly deficient in their ability to differentiate into Th17 cells both in vitro and in vivo in a T cell-intrinsic manner. Therefore, our study establishes T cell-expressed SLAT/Def6 as a pivotal positive regulator of Th17 inflammatory responses and, thus, essential in controlling autoimmune and inflammatory diseases. E xperimental autoimmune encephalomyelitis (EAE) 4 is a CD4 ϩ T cell-mediated disease of the CNS that is commonly used as an animal model of multiple sclerosis (MS), the most common demyelinating disease of the human CNS. Indeed, EAE shares significant similarities with human MS in its clinical course and pathological features (1), characterized by the invasion of self-reactive Th cells into the CNS, leading to demy-elination, axonal loss, and relapsing/remitting or chronic progressive paralysis. Upon activation, CD4 ϩ cells differentiate into three subsets of helper T cells, namely, Th1, Th2 and Th17, based on their distinct cytokine expression profiles and their subsequent immune regulatory functions (2– 4). Th1 cells mainly secrete IL-2 and IFN-␥ and mediate defense against infection by intracellular pathogens, and an overactive Th1 response can lead to autoimmu-nity. Th17 cells produce IL-17, IL-17F, IL-21, and IL-22, all of which regulate tissue inflammatory responses, and have been shown to be critical for enhancing host protection against extra-cellular bacteria and fungi (3–7). Furthermore, Th17 cells have been shown to have critical functions in the pathogenesis of a variety of organ-specific autoimmune …