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, peripheral blood mononuclear cells from 67 participants were analyzed at baseline and months one, three, and six. Flow cytometry quantified CD4+CD319+ and CD8+CD319+ T cells, cytotoxic and activation markers, and stimulated intracellular interleukin-4 (IL-4), IL-17A, and interferon-γ (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 five healthy controls and eight patients with SSc.

RESULTS

At baseline, CD319+ T cells showed greater cytokine production, activation, and granzyme and 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 six; placebo did not. Effects were strongest in patients in the fibroproliferative group, in whom 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 three (P = 0.0468 and P = 0.0287) and IL-17A in CD8+CD319+ T cells at month six (P = 0.0004), whereas 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 profibrotic and proinflammatory cytokines, particularly in the fibroproliferative subtype, in which CD319+ T cell reductions correlate with clinical improvement.