| First Author | Raynor JL | Year | 2024 |
| Journal | Immunity | Volume | 57 |
| Issue | 11 | Pages | 2597-2614.e13 |
| PubMed ID | 39406246 | Mgi Jnum | J:358114 |
| Mgi Id | MGI:7779478 | Doi | 10.1016/j.immuni.2024.09.013 |
| Citation | Raynor JL, et al. (2024) CRISPR screens unveil nutrient-dependent lysosomal and mitochondrial nodes impacting intestinal tissue-resident memory CD8(+) T cell formation. Immunity |
| abstractText | 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 intestine. Mechanistically, the Flcn-Tfeb axis restrained retinoic acid-induced CCR9 expression for migration and transforming growth factor beta (TGF-beta)-mediated programming for lineage differentiation. Genetic interaction screening revealed that the mitochondrial protein Mrpl52 enabled early T(RM) cell formation, while Acss1 controlled T(RM) cell development under Flcn deficiency-associated lysosomal dysregulation. Thus, the interplay between nutrients, organelle signaling, and metabolic adaptation dictates tissue immunity. |
