Background/Purpose: 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. We aimed to identify IL-23R⁺ T cells in the secondary lymphoid organs 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, and IL-23R^GFP/GFP (IL-23RKO) mice were immunized 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 the joints. The spleen, inguinal and popliteal lymph nodes (LN) were collected and analyzed for the expression of GFP⁺/IL-23R⁺ T cells. To study which T cells drive AIA, CCR6⁺CD4⁺ T cells and γδ T cells from CFA/mBSA immunized 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. Furthermore, the fraction and total CD4⁺ and TCRγδ⁺ cell counts were lower in IL-23RKO joints at day 4 of AIA. In vitro, cells of IL-23RKO mice produced less IL-17A. 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 naïve 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 arthritis induction, the fraction IL-23R⁺ CCR6⁺CD4⁺ T cells was increased in the draining LNs from the joints. The fraction of these IL-23R⁺ T cells decreased gradually during the progression of disease, possibly due to their migration towards the synovium. Adoptively transferred CCR6⁺CD4⁺ T cells, but not γδ T cells, were able

Conclusion: The IL-23R signaling pathway is essential for full-blown AIA. CCR6⁺CD4⁺ T cells and γδ T cells, but not CD8⁺ T cells, express IL-23R during naïve and inflammatory conditions. Interestingly, adoptive transfer of CCR6⁺CD4⁺ T cells but not γδ T cells, can rescue arthritis in IL-23R deficient mice.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ccr6cd4-t-cells-drive-il-23r-signaling-dependent-progression-of-antigen-induced-arthritis/