Bhlhe40 maintains CD8+ T cell fitness and functionality in non-lymphoid tissues and tumors

Abstract

Abstract Recent evidence has suggested that tissue-resident and tumor-infiltrating CD8 T cells share common molecular signatures for their maintenance in the non-lymphoid environment. Currently, the molecular mechanisms regulating the residency, health and function of effector and memory CD8 T cells in non-lymphoid tissue remain largely elusive. Here we have identified that the transcription factor Bhlhe40 is critical for the fitness and function of effector & memory CD8 T cells in the non-lymphoid tissue and tumor. Bhlhe40 and its associated gene signature are highly expressed in CD8 T cells, which reside in non-lymphoid tissues and tumor, compared with their counterparts in the spleen following viral infection and tumor transplantation. We find that Bhlhe40 deficiency results in the progressive loss of effector and memory CD8 T cells in non-lymphoid tissues following influenza infection and tumor transplantation. As such, Bhlhe40 abolition leads to defective anti-cancer immunity and impaired heterologous anti-viral immunity mediated by the tissue-resident effector and memory CD8 T cells. Mechanistically, we show that Bhlhe40 is dispensable for the activation and metabolic programming of CD8 T cells, but is vital for them maintaining metabolic and mitochondrial fitness. As such, Bhelhe40 deficiency results in energy failure of CD8 T cells and impaired maintenance of active histone marks in the loci of CD8 T cell effector molecules. Therefore, we have identified Bhlhe40 as a key TF for the maintenance of CD8 T cell fitness and functionality in non-lymphoid tissues. Furthermore, our data suggest that the manipulation of Bhlhe40 expression and function may serve as a potential strategy to boost the efficacy of vaccination and immunotherapy.