title: Th17 cells, not IL-17+ γδ T cells, drive arthritic bone destruction in mice and humans.
abstract: The mechanism whereby IL-17 drives rheumatoid arthritis remains incompletely understood. We demonstrate that anti-IL-17 therapy in collagen-induced arthritis ameliorates bone damage by reducing the number of osteoclasts in joints. We found equal numbers of CD4(+) Th17 and IL-17 producing γδ T cells in the joints of arthritic mice, and in vitro, both populations similarly induced osteoclastogenesis. However, individual depletion and adoptive transfer studies revealed that in vivo, Th17 cells dominated with regard to bone destruction. Unlike γδ T cells, Th17 cells were found in apposition to tartrate-resistant acid phosphatase positive osteoclasts in subchondral areas of inflamed joints, a pattern reproduced in patient biopsies. This localization was caused by Ag-specific retention, because OVA-primed Th17 cells showed a γδ T cell-like diffuse distribution. Because IL-23, as produced by osteoclasts, enhanced T cell-mediated osteoclastogenesis, we propose that Ag-specific juxtaposition is key to foster the molecular cross talk of Th17 cells and osteoclasts, thus driving arthritic bone destruction.
authors.affiliation: Department of Autoimmunity, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Pöllinger
authors.forename: Tobias
authors.initials: T
authors.lastname: Junt
authors.forename: Barbara
authors.initials: B
authors.lastname: Metzler
authors.forename: Ulrich A
authors.initials: UA
authors.lastname: Walker
authors.forename: Alan
authors.initials: A
authors.lastname: Tyndall
authors.forename: Cyril
authors.initials: C
authors.lastname: Allard
authors.forename: Serkan
authors.initials: S
authors.lastname: Bay
authors.forename: Roland
authors.initials: R
authors.lastname: Keller
authors.forename: Friedrich
authors.initials: F
authors.lastname: Raulf
authors.forename: Franco
authors.initials: F
authors.lastname: Di Padova
authors.forename: Terrence
authors.initials: T
authors.lastname: O'Reilly
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Horwood
authors.forename: Dhavalkumar D
authors.initials: DD
authors.lastname: Patel
authors.forename: Amanda
authors.initials: A
authors.lastname: Littlewood-Evans
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002358:Cartilage, Articular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D018920:Coculture Techniques; D024043:Collagen Type II / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged; D010010:Osteoclasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000096:biosynthesis*; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
chemical_list: D024043:Collagen Type II; D020381:Interleukin-17; D016692:Receptors, Antigen, T-Cell, gamma-delta