title: Control of Schistosoma mansoni egg-induced inflammation by IL-4-responsive CD4(+)CD25(-)CD103(+)Foxp3(-) cells is IL-10-dependent.
abstract: Host protection to helminth infection requires IL-4 receptor α chain (IL-4Rα) signalling and the establishment of finely regulated Th2 responses. In the current study, the role of IL-4Rα-responsive T cells in Schistosoma mansoni egg-induced inflammation was investigated. Egg-induced inflammation in IL-4Rα-responsive BALB/c mice was accompanied with Th2-biased responses, whereas T-cell-specific IL-4Rα-deficient BALB/c mice (iLck(cre)Il4ra(-) (/lox)) developed Th1-biased responses with heightened inflammation. The proportion of Foxp3(+) Treg in the draining LN of control mice did not correlate with the control of inflammation and was reduced in comparison to T-cell-specific IL-4Rα-deficient mice. This was due to IL-4-mediated inhibition of CD4(+)Foxp3(+) Treg conversion, demonstrated in adoptively transferred Rag2(-) (/) (-) mice. Interestingly, reduced footpad swelling in Il4ra(-) (/lox) mice was associated with the induction of IL-4 and IL-10-secreting CD4(+)CD25(-)CD103(+)Foxp3(-) cells, confirmed in S. mansoni infection studies. Transfer of IL-4Rα-responsive CD4(+)CD25(-)CD103(+) cells, but not CD4(+)CD25(high) or CD4(+)CD25(-)CD103(-) cells, controlled inflammation in iLck(cre)Il4ra(-) (/lox) mice. The control of inflammation depended on IL-10, as transferred CD4(+)CD25(-)CD103(+) cells from IL-10-deficient mice were not able to effectively downregulate inflammation. Together, these results demonstrate that IL-4 signalling in T cells inhibits Foxp3(+) Treg in vivo and promotes CD4(+)CD25(-)CD103(+)Foxp3(-) cells that control S. mansoni egg-induced inflammation via IL-10.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB) and Institute of Infectious Disease and Molecular Medicine (IIDMM), Division of Immunology, University of Cape Town, 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: William G C
authors.initials: WG
authors.lastname: Horsnell
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D039001:Integrin alpha Chains / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012313:RNA / Q000737:chemistry / Q000235:genetics; D011956:Receptors, Cell Surface / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012550:Schistosoma mansoni / Q000276:immunology*; D012555:Schistosomiasis mansoni / Q000276:immunology* / Q000469:parasitology; D015398:Signal Transduction / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D015703:Antigens, CD; D051858:Forkhead Transcription Factors; D039001:Integrin alpha Chains; D016753:Interleukin-10; D053645:Interleukin-2 Receptor alpha Subunit; D015847:Interleukin-4; D012313:RNA; D011956:Receptors, Cell Surface; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C091367:alpha E integrins