Breakdown in repression of IFN-γ mRNA leads to accumulation of self-reactive effector CD8⁺ T cells

Tight regulation of virus-induced cytotoxic effector CD8⁺ T cells is essential to prevent immunopathology. Naturally occurring effector CD8⁺ T cells, with a KLRG1^hi CD62L^lo phenotype typical of short-lived effector CD8⁺ T cells (SLECs), can be found in increased numbers in autoimmune-prone mice, most notably in mice homozygous for the san allele of Roquin. These SLEC-like cells were able to trigger autoimmune diabetes in a susceptible background. When Roquin is mutated (Roquin ^san), effector CD8⁺T cells accumulate in a cell-autonomous manner, most prominently as SLEC-like effectors. Excessive IFN-γ promotes the accumulation of SLEC-like cells, increases their T-bet expression, and enhances their granzyme B production in vivo. We show that overexpression of IFN-γ was caused by failed posttranscriptional repression of Ifng mRNA. This study identifies a novel mechanism that prevents accumulation of self-reactive cytotoxic effectors, highlighting the importance of regulating Ifng mRNA stability to maintain CD8⁺ T cell homeostasis and prevent CD8-mediated autoimmunity.