Ferroptosis exacerbates the clonal deletion of virus-specific exhausted CD8T cells.

Abstract

During chronic infection or tumorigenesis, persistent antigen stimulation contributes to the exhaustion of CD8T cells. Nevertheless, exhausted CD8T (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 Tcells, mechanisms underpinning the clonal deletion of Tcells 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 Tcells 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 Tcells. On the other hand, inhibiting ferroptosis via administration of a ferroptosis inhibitor or overexpression of GPX4 greatly rectified the cell loss of virus-specific Tcells. Collectively, we disclosed ferroptosis as a crucial player in the clonal deletion of virus-specific Tcells and stressed the intervention of ferroptosis as a promising approach to optimize the longevity of virus-specific Tcells.