CD8+ T cells drive myofibroblast activation and contraction via JAK/STAT3 and TGFβ signaling

Fibrosis in rheumatic connective tissue diseases is marked by CD8⁺ T cell and pro-fibrotic myofibroblast infiltration, though the role of CD8⁺ T cells in myofibroblast activity remains unexplored. To address this, we developed a 3D cell culture model of immunity-driven fibrosis by combining the classic mixed lymphocyte reaction and a 3D myofibroblast contractility model. Upon co-culture with myofibroblasts, CD8⁺ T cells more strongly induced myofibroblast contraction and activation than CD4⁺ T cells. This was not associated with cytotoxicity but with increased IL-6 production by CD8⁺ T cells and pSTAT3 and TGFβ signaling in myofibroblasts. Use of the JAK/STAT3-inhibitor tofacitinib or the TGFβ receptor inhibitor SB-505124 inhibited the activated myofibroblast phenotype, and combined use of both inhibitors had a clear additive effect. Our findings reveal a previously underappreciated non-canonical role of CD8⁺ T cells in fibrosis, providing new light to the mechanisms of the human immune system.