title: γδ T cell subsets play opposing roles in regulating experimental autoimmune encephalomyelitis.
abstract: γδ T cells are resident in cerebrospinal fluid and central nervous system (CNS) lesions of multiple sclerosis (MS) patients, but as multifaceted cells exhibiting innate and adaptive characteristics, their function remains unknown. Previous studies in experimental autoimmune encephalomyelitis (EAE) are contradictory and identified these cells as either promoting or suppressing disease pathogenesis. This study examines distinct γδ T cell subsets during EAE and indicates they mediate differential functions in CNS inflammation and demyelination resulting in pathogenesis or protection. We identified two γδ subsets in the CNS, Vγ1(+) and Vγ4(+), with distinct cytokine profiles and tissue specificity. Anti-γδ T cell receptor (TCR) monoclonal antibody (mAb) administration results in activation and downregulation of surface TCR, rendering the cells undetectable, but with opposing effects: anti-Vγ4 treatment exacerbates disease whereas anti-Vγ1 treatment is protective. The Vγ4(+) subset produces multiple pro-inflammatory cytokines including high levels of IL-17, and accounts for 15-20% of the interleukin-17 (IL-17) producing cells in the CNS, but utilize a variant transcriptional program than CD4(+) Th17 cells. In contrast, the Vγ1 subset produces CCR5 ligands, which may promote regulatory T cell differentiation. γδ T cell subsets thus play distinct and opposing roles during EAE, providing an explanation for previous reports and suggesting selective targeting to optimize regulation as a potential therapy for MS.
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Blink
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Caldis
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States.
authors.forename: Gwendolyn E
authors.initials: GE
authors.lastname: Goings
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Harp
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Case 906, Institut National de la Santé et de la Recherche Médicale, U631, Centre National de la Recherche Scientifique, UMR6102, 13288 Marseille, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Malissen
authors.affiliation: Hannover Medical School, Institute for Immunology, 30625 Hannover, Germany.
authors.forename: Immo
authors.initials: I
authors.lastname: Prinz
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States.
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States. Electronic address: s-d-miller@northwestern.edu.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D002454:Cell Differentiation / Q000276:immunology; D002490:Central Nervous System / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D015536:Down-Regulation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000276:immunology; D009836:Oligodendroglia / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D019713:Receptors, CCR5 / Q000096:biosynthesis; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D020381:Interleukin-17; D016692:Receptors, Antigen, T-Cell, gamma-delta; D019713:Receptors, CCR5
keywords: Adaptive immunity; Autoimmunity; Experimental autoimmune encephalomyelitis; Innate immunity; Multiple sclerosis; T cells; γδ T cells