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Background The IL-23/IL-17A immune pathway is important for the progression of T cell-mediated arthritis. However, it is not known where IL-23R+ T cells locate during the different stages of arthritis and which IL-23R+ T cells drive joint inflammation. Objectives We aimed to identify IL-23R+ T cells in the secondary lymphoid organs and synovium during the development and progression of antigen-induced arthritis (AIA). Furthermore, we studied which IL-23R+ T cells drive full-blown AIA. Methods To induce AIA, IL-23R+/+ (WT), heterozygous IL-23R+/GFP (IL-23R-GFP. KI reporter), and IL-23RGFP/GFP (IL-23RKO) mice were immunised with methylated bovine serum albumin (mBSA) in Complete Freund’s Adjuvant. After 7 days mice were injected in the knee joints with mBSA. Mice were macroscopically scored at different time points and knees were used for histological analysis of inflammation and bone erosion. The spleen, inguinal and popliteal lymph nodes (LN), and the synovium were collected and analysed for the expression of GFP+/IL-23R+ T cells. To study which T cells drive AIA, CCR6+ T helper (CD4+) cells and γδ T cells from CFA/mBSA immunised WT mice were adoptively transferred into IL-23RKO recipient mice prior to AIA induction and disease severity was assessed at the peak of AIA. Results AIA disease progression was mainly driven by the IL-23R pathway since IL-23RKO mice had significantly lower arthritis scores and less bone damage. During arthritis, total cell numbers of lymphoid tissues were lower in IL-23RKO mice, suggesting involvement of IL-23R pathway in cell proliferation. Heterozygous IL-23R reporter mice had similar disease scores to WT mice, indicating that half of the receptor expression is sufficient to drive disease. Flow cytometric analysis of GFP/IL-23R in T cells of naive and arthritic IL-23R reporter mice revealed that a fraction of CCR6+CD4+ T cells and γδ T cells, but not CD8+ T cells, expressed IL-23R in the lymphoid tissues. Already one day after AIA induction, the fractions of both IL-23R+ CCR6+CD4+ T cells and γδ T cells were increased in the draining LNs from the joints. However, these IL-23R+ T cells were decreased during the peak of disease, possibly due to their migration towards the synovium. Indeed, CD4+ T cells and γδ T cells were abundantly present in the WT joints during the peak of disease, but decreased in IL-23RKO joints. Adoptively transferred CCR6+CD4+ T cells, but not γδ T cells, were able to restore AIA in IL-23RKO mice, indicating that CCR6+CD4+ T cells are the main drivers of AIA. Conclusions The IL-23R signalling pathway is essential for full-blown AIA. Both CCR6+CD4+ T cells and γδ T cells, but not CD8+ T cells, express IL-23R during naive and inflammatory conditions. Total cell number in the lymphoid tissues of arthritic IL-23R deficient mice is lower. Interestingly, adoptive transfer of CCR6+CD4+ T cells but not γδ T cells, can rescue arthritis in IL-23R deficient mice. Disclosure of Interest None declared |
