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

Abstract

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.