IL-4Rα responsiveness of non-CD4 T cells contributes to resistance in Schistosoma mansoni infection in pan-T cell-specific IL-4Rα-deficient mice

Abstract

Interleukin (IL)-4 and IL-13 are T helper 2 cytokines whose biological functions are induced through a common IL-4 receptor α chain (IL-4Rα). CD4+ T cell-specific IL-4Rα-mediated signaling drives susceptibility to Leishmania major infection, but is not essential to host survival following Schistosoma mansoni infection. Here we generated a novel mouse model lacking IL-4Rα expression specifically on all T cells (iLckcreIl4ra-/lox), which was compared with CD4 + T cell-specific IL-4Rα-deficient mice (Lck creIl4ra-/lox), to investigate the possible roles of IL-4Rα responsive non-CD4+ T cells during either L. major or S. mansoni infection. Our results demonstrate a successful generation of transgene-bearing hemizygous iLckcreIl4ra-/lox BALB/c mice that have effective deletion of IL-4Rα on all T-cell populations. We show that iLckcreIl4ra-/lox mice infected with L. major developed a healing disease phenotype as previously observed in Lck creIl4ra-/lox mice, demonstrating that absence of IL-4Rα-responsive non-CD4+ in addition to CD4+ T cells does not further affect transformation of BALB/c to a healer phenotype. In acute schistosomiasis, however, iLckcreIl4ra-/lox mice showed enhanced mortality compared with Il4ra-/lox and Lck creIl4ra-/lox mice. iLckcreIl4ra -/lox mice died with similar kinetics to highly susceptible Il4ra-/- mice, despite controlling gut inflammation. In addition, iLckcreIl4ra-/lox mice presented increased liver granuloma sizes, as compared with LckcreIl4ra-/lox mice, with similar eosinophils, fibrosis, and liver damage. In conclusion, IL-4Rα-responsive non-CD4+ T cells prolong survival to acute schistosomiasis and contribute to the better control of hepatic granulomatous inflammation. Copyright © American Society for Investigative Pathology.