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

Autor:	Raynor JL; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Collins N; Metaorganism Immunity Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Shi H; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Guy C; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Saravia J; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Ah Lim S; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Chapman NM; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Zhou P; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Wang Y; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Sun Y; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Risch I; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Hu H; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Kc A; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Sun R; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Shrestha S; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Huang H; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Connelly JP; Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Pruett-Miller SM; Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Reina-Campos M; School of Biological Sciences, Department of Molecular Biology, University of California, San Diego, San Diego, CA, USA; La Jolla Institute for Immunology, La Jolla, CA 92037, USA., Goldrath AW; School of Biological Sciences, Department of Molecular Biology, University of California, San Diego, San Diego, CA, USA., Belkaid Y; Metaorganism Immunity Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Chi H; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: hongbo.chi@stjude.org.
Jazyk:	angličtina
Zdroj:	Immunity [Immunity] 2024 Nov 12; Vol. 57 (11), pp. 2597-2614.e13. Date of Electronic Publication: 2024 Oct 14.
DOI:	10.1016/j.immuni.2024.09.013
Abstrakt:	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 β (TGF-β)-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. Competing Interests: Declaration of interests H.C. consults or consulted for Kumquat Biosciences, Inc.; TCura Bioscience; Chugai Pharmaceuticals; and ONO Pharmaceutical Co and is a co-inventor on patents/patent applications in the fields of immunotherapy. A.W.G. serves on the scientific advisory boards of ArsenalBio and Foundery Innovations. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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