title: IL-7/IL-7 Receptor Signaling Differentially Affects Effector CD4+ T Cell Subsets Involved in Experimental Autoimmune Encephalomyelitis.
abstract: IL-17-producing CD4(+) T (Th17) cells, along with IFN-γ-expressing Th1 cells, represent two major pathogenic T cell subsets in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). The cytokines and transcription factors involved in the development and effector functions of Th1 and Th17 cells have been largely characterized. Among them, IL-23 is essential for the generation of stable and encephalitogenic Th17 cells and for the development of EAE. The IL-7/IL-7R signaling axis participates in cell survival, and perturbation of this pathway has been associated with enhanced susceptibility to MS. A link between IL-23-driven pathogenic T cells and IL-7/IL-7R signaling has previously been proposed, but has not been formally addressed. In the current study, we showed that Th17 cells from mice with EAE express high levels of IL-7Rα compared with Th1 cells. Using mice that constitutively express IL-7Rα on T cells, we determined that sustained IL-7R expression in IL-23R-deficient mice could not drive pathogenic T cells and the development of EAE. IL-7 inhibited the differentiation of Th17 cells, but promoted IFN-γ and GM-CSF secretion in vitro. In vivo IL-7/anti-IL-7 mAb complexes selectively expanded and enhanced the proliferation of CXCR3-expressing Th1 cells, but did not impact Th17 cells and EAE development in wild-type and IL-23R-deficient mice. Importantly, high IL-7 expression was detected in the CNS during EAE and could drive the plasticity of Th17 cells to IFN-γ-producing T cells. Together, these data address the contribution of IL-23/IL-23R and IL-7/IL-7R signaling in Th17 and Th1 cell dynamics during CNS autoimmunity.
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98101; Immunology Program, Benaroya Research Institute, Seattle, WA 98101;
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Arbelaez
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98101; Immunology Program, Benaroya Research Institute, Seattle, WA 98101;
authors.forename: Simon
authors.initials: S
authors.lastname: Glatigny
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98101; Immunology Program, Benaroya Research Institute, Seattle, WA 98101;
authors.forename: Rebekka
authors.initials: R
authors.lastname: Duhen
authors.affiliation: Lymphoid Tissue Development Unit, Pasteur Institute, Paris 75724, France; and.
authors.forename: Gerard
authors.initials: G
authors.lastname: Eberl
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98101; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Oukka
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98101; Immunology Program, Benaroya Research Institute, Seattle, WA 98101; ebettelli@benaroyaresearch.org.
authors.forename: Estelle
authors.initials: E
authors.lastname: Bettelli
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053759:Interleukin-23 / Q000276:immunology / Q000378:metabolism; D015851:Interleukin-7 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D053759:Interleukin-23; D015851:Interleukin-7; D018123:Receptors, Interleukin; D020395:Receptors, Interleukin-7; C528688:interleukin-23 receptor, mouse; D007371:Interferon-gamma