Background/Purpose: CD4⁺ T cells can differentiate into functionally distinct subsets and play a pivotal role in rheumatoid arthritis (RA). Th22 cells have been identified as a new subset secreting IL-22. Although elevated levels of IL-22 in the synovial fluids of RA patients were reported, its pathological roles remain unclear. In this study, we examined the function of human Th22 cells, the distribution of Th22 cells in synovial tissues in RA patients, and the influences of Th22 cells on osteoclast differentiation in order to elucidate the role of Th22 cells in RA pathogenesis.

Methods: CD3⁺ CD4⁺ CXCR3⁺ CCR6^– (Th1) cells, CD3⁺ CD4⁺ CXCR3⁻ CCR4⁺ CCR6⁺ CCR10⁻ (Th17) cells, and CD3⁺ CD4⁺ CXCR3⁻ CCR4⁺ CCR6⁺ CCR10⁺ (Th22) cells were sorted from the peripheral blood of healthy individuals and the ability of these subsets to produce cytokines were compared. CD3⁺CD4⁺IL-22⁺IL-17^–IFN-γ^–Th22 cells and chemokine receptor-ligands (CCL17, CCL20, CCL28) in synovial tissues in patients with RA and osteoarthritis (OA) were evaluated by immunohistochemistry. Human monocytes were cultured with IL-22, IL-17 or IFN-γ in the presence of M-CSF and RANKL for 12 days. Th1 cells, Th17 cells or Th22 cells were sorted from peripheral blood and co-cultured with monocytes in the presence of M-CSF and RANKL.

Results: CD3⁺ CD4⁺ CCR4⁺ CCR6⁺ CCR10⁺ cells produced neither IFN-γ nor IL-17, but characteristically produced IL-22 alone, and that their ability to produce IL-22 exceeded that of other helper T cell subsets. Th22 cells were markedly infiltrated in synovial tissue in patients with active RA, but not in patients with OA. CCL17, CCL20 and CCL28 were abundantly expressed in RA synovial tissue compared to OA. Actually, by in vitro Trans-well migration assay, Th22 cells efficiently migrated towards CCL28. Addition of IL-22 to the in vitro culture of monocytes with M-CSF and RANKL markedly increased numbers of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts formation. Contrarily, the addition of IFN-γ to the culture significantly decreased TRAP-positive osteoclasts number, whereas IL-17 had marginal effects. The gene expression of NFATc1 and cathepsin K was significantly increased by addition of IL-22 to the culture in a dose dependent manner. Co-culture of Th22 cells, which were sorted from peripheral blood, with monocytes in the presence of M-CSF and RANKL induced TRAP-positive osteoclasts formation more efficiently than that of either Th1 cells or Th17 cells. IL-22 neutralizing antibody completely inhibited osteoclast formation in co-culture of Th22 cells with monocytes.

Conclusion: Th22 cells, which co-express chemokine receptors CCR4, CCR6 and CCR10, possess strong potency of tissue migration and accumulate into inflamed synovial tissues where the ligands such as CCL28 are highly expressed. The results indicated that Th22 cells have the capacity to promote osteoclast differentiation through production of IL-22. Thus, Th22 cells may play a pivotal role in the pathogenesis of RA by bone resorption in RA synovitis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/th22-cells-are-a-potent-inducer-of-osteoclastogenesis-in-rheumatoid-arthritis/