Mechanistic studies on the regulation of systemic sclerosis progression by imbalance in angiogenic T cell subsets

Vasculopathy is a core pathological feature of systemic sclerosis (SSc), but its immune regulatory mechanisms remain incompletely understood. In particular, the expression patterns, clinical relevance, and functional roles of CD8⁺CD28^- and CD8⁺CD28⁺ angiogenic T cell (Tang) subpopulations in SSc have not been fully defined. This study aimed to systematically investigate the distribution, clinical significance, and molecular characteristics of these Tang subsets in SSc. We identified CD8⁺ Tang subpopulations in the lung tissue of patients with SSc-associated interstitial lung disease (SSc-ILD), with a gradual decrease in CD28-related signals along the inferred differentiation trajectory. In the peripheral blood of patients with SSc, CD8⁺CD28^- Tang were increased, whereas CD8⁺CD28⁺ Tang were decreased. These alterations were associated with vascular complications, including ILD, digital ulcers, and advanced microvascular lesions, as well as with disease activity, and may serve as biomarkers of treatment response. Functional experiments showed that CD8⁺CD28^- Tang impaired endothelial cell proliferation, migration, tube formation, and survival through a GZMB-dependent mechanism associated with reduced Akt activation, whereas CD8⁺CD28⁺ Tang exerted protective effects through VEGF/AREG-related activation of EGFR/Erk signaling. In summary, our data support an association between CD8⁺CD28^-/CD8⁺CD28⁺ Tang imbalance and clinical parameters of vasculopathy in SSc, while in vitro findings indicate distinct endothelial-injurious and endothelial-protective functions of these two subsets, suggesting that they may contribute to vascular dysfunction in SSc.