CRISPR screens unveil nutrient-dependent lysosomal and mitochondrial nodes impacting intestinal tissue-resident memory CD8⁺ T cell formation.

ABSTRACT: Nutrient availability and organelle biology direct tissue homeostasis and cell fate, but how these processes orchestrate tissue immunity remains poorly defined. Here, using in vivo CRISPR-Cas9 screens, we uncovered organelle signaling and metabolic processes shaping CD8⁺ tissue-resident memory T (T_RM) cell development. T_RM cells depended on mitochondrial translation and respiration. Conversely, three nutrient-dependent lysosomal signaling nodes-Flcn, Ragulator, and Rag GTPases-inhibited intestinal T_RM cell formation. Depleting these molecules or amino acids activated the transcription factor Tfeb, thereby linking nutrient stress to T_RM programming. Further, Flcn deficiency promoted protective T_RM cell responses in the small

SUBMITTER: Raynor JL 

PROVIDER: S-EPMC11590283 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature