IL-4Rα Responsiveness of Non-CD4 T Cells Contributes to Resistance in Schistosoma mansoni Infection in Pan-T Cell-Specific IL-4Rα-Deficient Mice

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 (LckcreIl4ra−/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 LckcreIl4ra−/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 LckcreIl4ra−/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.