Semaphorin 3E Promotes Susceptibility to Infection in Mice by Suppressing CD4 Th1 Cell Response.

Protective immunity to cutaneous leishmaniasis is mediated by IFN-γ-secreting CD4 Th1 cells. IFN-γ binds to its receptor on -infected macrophages, resulting in their activation, production of NO, and subsequent destruction of parasites. This study investigated the role of Semaphorin 3E (Sema3E) in host immunity to infection in mice. We observed a significant increase in Sema3E expression at the infection site at different timepoints following infection. Sema3E-deficient (Sema3E knockout [KO]) mice were highly resistant to infection, as evidenced by significantly ( < 0.05-0.01) reduced lesion sizes and lower parasite burdens at different times postinfection when compared with their infected wild-type counterpart mice. The enhanced resistance of Sema3E KO mice was associated with significantly ( < 0.05) increased IFN-γ production by CD4 T cells. CD11c cells from Sema3E KO mice displayed increased expression of costimulatory molecules and IL-12p40 production following infection and were more efficient at inducing the differentiation of -specific CD4 T cells to Th1 cells than their wild-type counterpart cells. Furthermore, purified CD4 T cells from Sema3E KO mice showed increased propensity to differentiate into Th1 cells in vitro, and this was significantly inhibited by the addition of recombinant Sema3E in vitro. These findings collectively show that Sema3E is a negative regulator of protective CD4 Th1 immunity in mice infected with and suggest that its neutralization may be a potential therapeutic option for treating individuals suffering from cutaneous leishmaniasis.