A CD4+ T cell-fibroblast crosstalk exacerbates autoimmunity in a mouse model of primary Sjögren disease

CD4+ T cells are key drivers of immune-mediated tissue damage and participate in complex cellular interactions that perpetuate chronic inflammation. However, the specific subsets of pathogenic CD4+ T cells and their non-immune cell partners are less well characterized. Here, we use a mouse model of primary Sjögren disease (pSjD) and identify CD153+CD4+ T cells as critical drivers of inflammation during the early stages of autoimmune pathology. We describe a CD153+CD4+ T cell-CD30+ tissue-resident fibroblast interaction that promotes fibroblast proliferation and chemokine secretion, further driving immune cell infiltration and thereby amplifying the autoimmune response. Importantly, deletion of CD153 in CD4+ T cells or neutralization of fibroblast-derived chemokines reduces lymphocytic infiltration and significantly halts autoimmune-like pathology. The CD153-CD30 axis positively correlates with disease severity in human patients. Thus, our results describe a pathogenic, therapeutically targetable CD153+CD4+ T cell-CD30+ fibroblast axis that perpetuates chronic inflammation in pSjD. CD4+ T cells are key drivers of chronic inflammation and immune-mediated tissue damage in autoimmune diseases. Here, the authors employ a mouse model of primary Sjögren disease (pSjD) and identify a subset of CD153+ CD4+ T cells responsible for inflammation and autoimmunity through interactions with CD30+ resident fibroblasts, and demonstrate that targeting the CD153-CD30 axis alleviates disease pathology in mice.