Ferroptosis exacerbates the clonal deletion of virus-specific exhausted CD8 T cells.

During chronic infection or tumorigenesis, persistent antigen stimulation contributes to the exhaustion of CD8 T cells. Nevertheless, exhausted CD8 T (T) cells still preserve certain effector function, and maintaining a reservoir of exhausted cells is of vital importance for virus elimination and tumor eradiation. Despite considerable work interrogating the rejuvenation of T cells, mechanisms underpinning the clonal deletion of T cells remain largely unexplored over the past decade. In this study, we employed mouse models of LCMV infection to demonstrate that excessive accumulation of lipid peroxidation rendered virus-specific T cells to ferroptosis, which may correlate with enhanced mitochondria-derived oxidative stress and compromised activity of glutathione peroxidase 4 (GPX4). In addition, either incomplete or complete ablation of GPX4 resulted in exacerbated ferroptosis and aggravated shrunken population of virus-specific T cells. On the other hand, inhibiting ferroptosis via administration of a ferroptosis inhibitor or overexpression of GPX4 greatly rectified the cell loss of virus-specific T cells. Collectively, we disclosed ferroptosis as a crucial player in the clonal deletion of virus-specific T cells and stressed the intervention of ferroptosis as a promising approach to optimize the longevity of virus-specific T cells.