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

摘要

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 (>iLck^>cre>Il4ra^>−/lox), which was compared with CD4⁺ T cell-specific IL-4Rα-deficient mice (>Lck^>cre>Il4ra^>−/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 >iLck^>cre>Il4ra^>−/lox BALB/c mice that have effective deletion of IL-4Rα on all T-cell populations. We show that >iLck^>cre>Il4ra^>−/lox mice infected with >L. major developed a healing disease phenotype as previously observed in >Lck^>cre>Il4ra^>−/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, >iLck^>cre>Il4ra^>−/lox mice showed enhanced mortality compared with >Il4ra^>−/lox and >Lck^>cre>Il4ra^>−/lox mice. >iLck^>cre>Il4ra^>−/lox mice died with similar kinetics to highly susceptible >Il4ra^−/− mice, despite controlling gut inflammation. In addition, >iLck^>cre>Il4ra^>−/lox mice presented increased liver granuloma sizes, as compared with >Lck^>cre>Il4ra^>−/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.