Abatacept Reduces CD319+ (SLAMF7) Cytotoxic T Cells and Cytokine Production in Systemic Sclerosis.

Abstract

Systemic sclerosis (SSc) is characterized by immune dysregulation and fibrosis. We investigated whether abatacept modulates CD319/SLAMF7-expressing cytotoxic T cells implicated in diffuse cutaneous SSc. In this ancillary ASSET trial analysis, PBMCs from 67 participants were analyzed at baseline and months 1, 3, and 6. Flow cytometry quantified CD4+CD319+ and CD8+CD319+ T cells, cytotoxic/activation markers, and stimulated intracellular IL-4, IL-17A, and IFN-γ. Analyses compared abatacept-treated molecular endotypes with placebo and related immune changes to modified Rodnan skin score (mRSS) change. Skin single-cell RNA sequencing included 5 healthy controls and 8 SSc patients. At baseline, CD319+ T cells showed greater cytokine production, activation, and granzyme/perforin expression than CD319- T cells in 60 evaluable participants (p<0.001 to p<0.0001). Abatacept reduced CD4+CD319+ and CD8+CD319+ T cell frequencies at month 6; placebo did not. Effects were strongest in fibroproliferative patients, where CD8+CD319+ T cells decreased versus placebo (n=7 versus n=36; p=0.0377). In this endotype, abatacept reduced IL-4 in CD4+CD319+ and CD8+CD319+ T cells at month 3 (p=0.0468 and p=0.0287) and IL-17A in CD8+CD319+ T cells at month 6 (p=0.0004), while IFN-γ was unchanged. Reduction in CD4+CD319+ T cells correlated with mRSS improvement in abatacept-treated patients (r=0.5297, p=0.0423). Skin single-cell RNA-sequencing showed increased SLAMF7 expression in SSc T cells (p=0.017), enriched within cytotoxic subsets. CD319+ T cells represent highly differentiated, activated cytotoxic effector populations in SSc. Abatacept selectively modulates these cells and suppresses associated pro-fibrotic and pro-inflammatory cytokines, particularly in the fibroproliferative subtype, where CD319+ T cell reductions correlate with clinical improvement.