Semaphorins in the immune system

One of the Class IV semaphorins, Sema4A, is expressed constitutively on dendritic cells (DCs) and induced on Th1-polarized cells but not on Th2-polarized cells. Sema4A binds to Tim-2, a member of the T cell immunoglobulin domain and mucin domain (Tim) protein family, whose expression is induced on activated T cells, and enhances in vitro activation and differentiation of T cells. To determine functions of Sema4A in vivo, Sema4A−/− mice have been generated. Sema4A−/− DCs show a reduced ability to stimulate allogeneic T cells. T cells from Sema4A−/− also fail to differentiate into Th1 cells in vitro in Th1-inducing conditions, although they can differentiate into Th2 cells in Th2-inducing conditions. Indeed, Sema4A−/− mice display defects not only in T cell priming but also in Th1 differentiation. When wild type mice are injected with antigen-pulsed Sema4A−/− DCs, proliferation and IL-2 secretion of antigen-specific T cells are severely impaired. On the other hand, generation of Th1 cells but not Th2 cells is impaired in Sema4A−/− mice that have been injected with antigen-pulsed wild-type DCs. These findings indicate that both DC-derived Sema4A and T cell-derived Sema4A are necessary for T cell activation and differentiation; the former is required for T cell priming and the latter for Th1 differentiation.