title: IL-4Ralpha responsiveness of non-CD4 T cells contributes to resistance in schistosoma mansoni infection in pan-T cell-specific IL-4Ralpha-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 alpha chain (IL-4Ralpha). CD4(+) T cell-specific IL-4Ralpha-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-4Ralpha expression specifically on all T cells (iLck(cre)Il4ra(-/lox)), which was compared with CD4(+) T cell-specific IL-4Ralpha-deficient mice (Lck(cre)Il4ra(-/lox)), to investigate the possible roles of IL-4Ralpha 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-4Ralpha 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-4Ralpha-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-4Ralpha-responsive non-CD4(+) T cells prolong survival to acute schistosomiasis and contribute to the better control of hepatic granulomatous inflammation.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB) University Campus, Room S1.27; Werner Beith South Wing, Observatory 7925, Cape Town, South Africa.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dewals
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Hoving
authors.forename: Mosiuoa
authors.initials: M
authors.lastname: Leeto
authors.forename: Reece G
authors.initials: RG
authors.lastname: Marillier
authors.forename: Umeshree
authors.initials: U
authors.lastname: Govender
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Cutler
authors.forename: William G C
authors.initials: WG
authors.lastname: Horsnell
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D006099:Granuloma / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology*; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000276:immunology; D008107:Liver Diseases / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D012550:Schistosoma mansoni; D012555:Schistosomiasis mansoni / Q000150:complications / Q000276:immunology* / Q000473:pathology
chemical_list: D053662:Interleukin-4 Receptor alpha Subunit