Naive CD8⁺T Cells Expressing CD95 Increase Human Cardiovascular Disease Severity

Objective: Cardiovascular disease (CVD) remains a significant global health concern with a high degree of mortality. While CD4⁺T cells have been extensively studied in CVD, the importance of CD8⁺T cells in this disease, despite their abundance and increased activation in human atherosclerotic plaques, remains largely unknown. Thus, the objective of this study was to compare peripheral T-cell signatures between humans with a high (severe) risk of CVD (including myocardial infarction or stroke) and those with a low risk of CVD. Approach and Results: Using mass cytometry, we uncovered a naive CD8⁺T (T_N) cell population expressing CD95 (termed CD95⁺CD8⁺stem cell memory T [CD8 T_SCM] cells) that was enriched in patients with high compared with low CVD. This T-cell subset enrichment within individuals with high CVD was a relative increase and resulted from the loss of CD95^locells within the T_Ncompartment. We found that CD8 T_SCMcells positively correlated with CVD risk in humans, while CD8⁺T_Ncells were inversely correlated. Atherosclerotic apolipoprotein E-deficient (ApoE^-/-) mice also displayed respective 7-and 2-fold increases in CD8⁺T_SCMfrequencies within the peripheral blood and aorta-draining paraaortic lymph nodes compared with C57BL/6J mice. CD8⁺T_SCMcells were 1.7-fold increased in aortas from western diet fed ApoE^-/-mice compared with normal laboratory diet-fed ApoE^-/-mice. Importantly, transfer of T_SCMcells into immune-deficient Rag.Ldlr recipient mice that lacked T cells increased atherosclerosis, illustrating the importance of these cells in atherogenesis. Conclusions: CD8⁺T_SCMcells are increased in humans with high CVD. As these T_SCMcells promote atherosclerosis, targeting them may attenuate atherosclerotic plaque progression.