title: Nippostrongylus-induced intestinal hypercontractility requires IL-4 receptor alpha-responsiveness by T cells in mice.
abstract: Gut-dwelling helminthes induce potent IL-4 and IL-13 dominated type 2 T helper cell (T(H)2) immune responses, with IL-13 production being essential for Nippostrongylus brasiliensis expulsion. This T(H)2 response results in intestinal inflammation associated with local infiltration by T cells and macrophages. The resulting increased IL-4/IL-13 intestinal milieu drives goblet cell hyperplasia, alternative macrophage activation and smooth muscle cell hypercontraction. In this study we investigated how IL-4-promoted T cells contributed to the parasite induced effects in the intestine. This was achieved using pan T cell-specific IL-4 receptor alpha-deficient mice (iLck(cre)IL-4Rα(-/lox)) and IL-4Rα-responsive control mice. Global IL-4Rα(-/-) mice showed, as expected, impaired type 2 immunity to N. brasiliensis. Infected T cell-specific IL-4Rα-deficient mice showed comparable worm expulsion, goblet cell hyperplasia and IgE responses to control mice. However, impaired IL-4-promoted T(H)2 cells in T cell-specific IL-4Rα deficient mice led to strikingly reduced IL-4 production by mesenteric lymph node CD4(+) T cells and reduced intestinal IL-4 and IL-13 levels, compared to control mice. This reduced IL-4/IL-13 response was associated with an impaired IL-4/IL-13-mediated smooth muscle cell hypercontractility, similar to that seen in global IL-4Rα(-/-) mice. These results demonstrate that IL-4-promoted T cell responses are not required for the resolution of a primary N. brasiliensis infection. However, they do contribute significantly to an important physiological manifestation of helminth infection; namely intestinal smooth muscle cell-driven hypercontractility.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB) and Division of Immunology, Institute of Infectious Disease and Molecular Medicine (IIDMM), Health Science Faculty, University of Cape Town, Cape Town, South Africa.
authors.forename: Saskia
authors.initials: S
authors.lastname: Schmidt
authors.forename: J Claire
authors.initials: JC
authors.lastname: Hoving
authors.forename: William G C
authors.initials: WG
authors.lastname: Horsnell
authors.forename: Helen
authors.initials: H
authors.lastname: Mearns
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Cutler
authors.forename: Tiroyaone Masego H.
authors.initials: TMH
authors.lastname: Bogale
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000276:immunology / Q000469:parasitology*; D051379:Mice; D009119:Muscle Contraction / Q000502:physiology; D009559:Nippostrongylus / Q000472:pathogenicity*; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D019948:Receptors, Interleukin-4