ExTh17 Cells Arising from Th17 Support Chronic RA-Like Inflammation Independent of IL-17 2260860

Abstract

Abstract Introduction T helper 17 (Th17) cells are present in both peripheral blood and synovial fluid of patients with rheumatoid arthritis (RA), yet IL-17-targeted therapies have shown limited efficacy in established disease. The role of IL-17 and Th17 cells in RA has not been completely clarified. Although inflammation can drive Th17 cells to transdifferentiate into IL-17-negative Th1- or Tr1-like so-called exTh17 cells, the role of these cells in arthritis remains unclear. Here, we investigate whether exTh17 cells contribute to joint inflammation in autoimmune arthritis. Methods Using Th17 lineage tracing in the SKG mouse model of RA, we demonstrate that synovial Th17 cells transdifferentiate into IFNγ- and IL-10-producing exTh17 cells, which become the dominant CD4+ T cell population in chronic arthritis. These exTh17 cells are more arthritogenic than Th17 cells and maintain synovial inflammation through IL-17-independent mechanisms involving elevated IL-6 and TNF, two key cytokines in RA pathogenesis. Synovial exTh17 cells analyzed by bulk, single-cell RNASeq, and Spatial transcriptomics exhibit a distinct gene expression profile, including upregulation of S1PR4, in CD4+ T cell profiles from mouse and human RA synovial tissue. We further show, using co-culture assays, that interaction between Th17 cells and fibroblast-like synoviocytes (FLS) via S1P signaling promotes Th17-to-exTh17 conversion. Results The pro-inflammatory environment of arthritis induces a population of exTh17 cells, promoting chronicity of arthritis without re-expression of IL-17. Blocking S1P—S1PR4 signaling inhibits their formation independently of lymph node T cell trafficking. Fibroblast-like synoviocytes (FLS) promote exTh17 generation via S1P production, and RA FLS are major S1P sources in both humans and mice. Conclusion These new insights open the door to more targeted therapeutic strategies beyond IL-17 inhibition. Funding Source n/a Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)