Interleukin 17-producing C-C motif chemokine receptor 6 + conventional CD4+ T cells are arthritogenic in an animal model of spondyloarthritis

Abstract

Objective: Spondyloarthritis (SpA) is a group of chronic inflammatory disorders associated with the human leukocyte antigen (HLA) class I allele HLA-B27. Transgenic rats expressing HLA-B27 and human β2-microglobulin (B27 rats) develop clinical manifestations resembling SpA called rat SpA. IL-17 and TNF are key proinflammatory cytokines implicated in both human and rat SpA. We aimed to determine which T cell subset(s) produce IL-17 and TNF during rat SpA, characterize their tissue distribution and tested their pathogenicity in vivo.

Methods: Cytokine production by T cell subsets was evaluated in target tissues and lymphoid organs during rat SpA. Pathogenicity of purified IL-17⁺ cells was assessed in vivo by cell transfer. Blood samples were used to translate B27 rats findings to SpA patients.

Results: Conventional CD4⁺ T cells (Foxp3^-; Tconv) and γδ T cells were the main producers of both IL-17 and TNF in B27 rats. IL-17-producing Tconv and γδ T cells were expanded in the colon of premorbid 3-weeks-old B27 rats. C-C motif chemokine receptor 6 (CCR6) allowed the isolation of IL-17⁺ Tconv (Th17) in rat. Transfer of B27 rat IL-17-producing CCR6⁺ Tconv but not of γδ T cells into disease-free nude B27 rats induced arthritis, directly demonstrating for the first time the arthritogenic potential of Th17 cells in SpA. Finally, a CCR6⁺ IL-17⁺ Tconv expansion enriched for IL-17F production was evidenced in SpA patients.

Conclusion: Our study demonstrates that IL-17⁺TNF⁺CCR6⁺ Th17 cells and IL-17⁺ γδ T cells are expanded preceding SpA onset in B27 rats and that only IL-17⁺TNF⁺CCR6⁺ Th17 cells can trigger arthritis.