Heightened protein synthesis and aggregation, coupled with futile protein quality control, underlie a novel mechanism of CD8+ T cell exhaustion 3479

Abstract Description T cell dysfunction or exhaustion in response to persistent antigen stimulation represents a hypofunctional state orchestrated by both genetic and epigenetic mechanisms. The contribution of dysregulated proteostasis to T cell exhaustion is unknown. Using high-resolution mass spectrometry (MS), we profiled the CD8+ T cell proteome in various exhaustion states. Our analysis revealed a heightened proteostatic stress response (PSR) in exhausted T cells across cancer and chronic infection models. Unlike canonical stress responses, this unique PSR in the exhaustive state of T cells (PSR-Tex) was marked unexpectedly by increased global protein translation, leading to further accumulation of misfolded proteins in the endoplasmic reticulum (ER) and upregulation of specific ER chaperones. We established the causality of protein misfolding in T cell exhaustion, demonstrating that induction of protein misfolding alone, without persistent T cell receptor stimulation, recapitulated the exhaustion phenotype. Mechanistically, we demonstrated Akt signaling as the pivotal instigator of PSR-Tex. In summary, our findings highlight a novel PSR-Tex response as a unique hallmark of exhausted T cells and provide a new therapeutic opportunity for cancer immunotherapy. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)