Balint Elizabeth, Adaimy Marie Joe, Montemarano Amelia, Portillo Ana L, Ashkar Ali A
McMaster Immunology Research Centre, Department of Medicine, McMaster University, Hamilton, ON, Canada.
Eur J Immunol. 2025 Jun;55(6):e51673. doi: 10.1002/eji.202451673.
The recent COVID-19 pandemic has highlighted a significant sex bias in disease outcome, where male sex is associated with greater disease severity and mortality. Interestingly, studies have also identified a role for antigen-independent "bystander-activated" CD8 T cells in the severity of COVID-19 and other viral infections. However, whether biological sex contributes to the magnitude of bystander T cell activation has not been investigated. To assess sex differences in bystander CD8 T cell activation, we isolated PBMCs from age-matched male and female donors and stimulated the cells with cytokines IL-12/15/18 to induce bystander T cell activation. Male CD8 T cells stimulated with IL-15 exhibited greater bystander activation, including increased NKG2D expression and greater antigen-independent cytotoxicity against tumor cells compared with female CD8 T cells. In contrast, IL-12/18 and IL-12/15/18 stimulation of CD8 T cells did not reveal evidence of sex differences in bystander IFN-γ production. Our data suggest that underlying sex differences in bystander CD8 T cell activation and cytotoxicity may contribute to the observed sex biases in disease severity of viral infections.
近期的新冠疫情凸显了疾病结局方面显著的性别偏差，即男性与更高的疾病严重程度和死亡率相关。有趣的是，研究还发现抗原非依赖性“旁观者激活”的CD8 T细胞在新冠及其他病毒感染的严重程度中发挥作用。然而，生物性别是否会影响旁观者T细胞激活的程度尚未得到研究。为了评估旁观者CD8 T细胞激活中的性别差异，我们从年龄匹配的男性和女性供体中分离出外周血单核细胞（PBMC），并用细胞因子IL-12/15/18刺激这些细胞以诱导旁观者T细胞激活。与女性CD8 T细胞相比，用IL-15刺激的男性CD8 T细胞表现出更强的旁观者激活，包括NKG2D表达增加以及对肿瘤细胞更强的抗原非依赖性细胞毒性。相比之下，用IL-12/18和IL-12/15/18刺激CD8 T细胞并未发现旁观者IFN-γ产生存在性别差异的证据。我们的数据表明，旁观者CD8 T细胞激活和细胞毒性中潜在的性别差异可能导致了在病毒感染疾病严重程度中观察到的性别偏差。
