Integrin 3 promotes T_H17 cell polarization and extravasation during autoimmune neuroinflammation

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) caused by CNS-infiltrating leukocytes, including T(H)17 cells that are critical mediators of disease pathogenesis. Although targeting leukocyte trafficking is effective in treating autoimmunity, there are currently no therapeutic interventions that specifically block encephalitogenic T(H)17 cell migration. Here, we report integrin alpha 3 as a T(H)17 cell-selective determinant of pathogenicity in experimental autoimmune encephalomyelitis. CNS-infiltrating T(H)17 cells express high integrin alpha 3, and its deletion in CD4( +) T cells or Il17a fate-mapped cells attenuated disease severity. Mechanistically, integrin alpha 3 enhanced the immunological synapse formation to promote the polarization and proliferation of T(H)17 cells. Moreover, the transmigration of T(H)17 cells into the CNS was dependent on integrin alpha 3, and integrin alpha 3 deficiency enhanced the retention of CD4 (+) T cells in the perivascular space of the blood-brain barrier. Integrin alpha 3-dependent interactions continuously maintain T(H)17 cell identity and effector function. The requirement of integrin alpha 3 in T(H)17 cell pathogenicity suggests integrin alpha 3 as a therapeutic target for MS treatment.