title: Th17 cells induce a distinct graft rejection response that does not require IL-17A.
abstract: IL-17A-producing helper T (Th17) cells have been implicated in the pathogenesis of autoimmune disease, inflammatory bowel disease and graft rejection, however the mechanisms by which they cause tissue damage remain ill-defined. We examined what damage Th17 cell lines could inflict on allogeneic skin grafts in the absence of other adaptive lymphocytes. CD4(+)  Th17 cell lines were generated from two TCR transgenic mouse strains, A1(M).RAG1(-/-)  and Marilyn, each monospecific for the male antigen Dby. After prolonged in vitro culture in polarizing conditions, Th17 lines produced high levels of IL-17A with inherently variable levels of interferon gamma (IFNγ) and these cells were able to maintain IL-17A expression following adoptive transfer into lymphopenic mice. When transferred into lymphopenic recipients of male skin grafts, Th17 lines elicited a damaging reaction within the graft associated with pathological findings of epidermal hyperplasia and neutrophil infiltration. Th17 cells could be found in the grafted skins and spleens of recipients and maintained their polarized phenotype both in vivo and after ex vivo restimulation. Antibody-mediated neutralization of IL-17A or IFNγ did not interfere with Th17-induced pathology, nor did it prevent neutrophil infiltration. In conclusion, tissue damage by Th17 cells does not require IL-17A.
authors.affiliation: University of Oxford, Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: E I
authors.initials: EI
authors.lastname: Agorogiannis
authors.forename: F S
authors.initials: FS
authors.lastname: Regateiro
authors.forename: D
authors.initials: D
authors.lastname: Howie
authors.forename: H
authors.initials: H
authors.lastname: Waldmann
authors.forename: S P
authors.initials: SP
authors.lastname: Cobbold
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005260:Female; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D008231:Lymphopenia / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D016038:Skin Transplantation; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D020381:Interleukin-17; D007371:Interferon-gamma