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

Objective

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.

Methods

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.

Results

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.

Conclusion

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.