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 a chain (IL-4R alpha). CD4(+) T cell-specific EL-4R alpha-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-4Ra expression specifically on all T cells (iLck(cre)Il4ra(-/lox)), which was compared with CD4(+) T cell-specific IL-4R alpha-deficient mice (Lck(cre)Il4ra(-/lox)), to investigate the possible roles of IL-4R alpha responsive non-CD4(+) T cells during either L major or S. mansoni infection. Our results demonstrate a successful generation of transgene-bearing hemizygous Lck(cre)Il4ra(-/lox) BALB/c mice that have effective deletion of IL-4R alpha 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 iLck(cre)Il4ra(-/lox) mice, demonstrating that absence of IL-4R alpha 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, Lck(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-4R alpha-responsive non-CD4(+) T cells prolong survival to acute schistosomiasis and contribute to the better control of hepatic granulomatous inflammation. (Ant J Pathol 2009, 175:706-716. DOI: 10.2353/ajpath.2009.090137)