Wednesday, April 2, 2025
4/2/2025
Regulation of T cell memory in tissue immunity - Program Summary/Abstract Tissue-resident memory T cells (TRM) are crucial for the frontline defense against pathogen infection and maintenance of tissue homeostasis. How T cells are fated for TRM development and targeted for residency in specific tissue sites remain poorly understood. The environmental cues that orchestrate metabolic adaptation for TRM development or maintenance are also unclear. These knowledge gaps represent substantial barriers to harnessing the full therapeutic potential of TRM cells in infectious disease and cancer. In our preliminary studies, using in vivo pooled CRISPR screening of mitochondria and lysosome-associated genes, we uncovered organelle signaling and metabolic processes shaping CD8+ TRM development. Specifically, three nutrient- dependent lysosomal signaling nodes, Flcn, Rag GTPases and Ragulator, potently inhibit TRM formation. Depleting these molecules or depriving amino acids activates transcription factor Tfeb, thereby linking nutrients to TRM programming. Further, Flcn deficiency promotes protective TRM responses against gastrointestinal pathogen infection. Mechanistically, Flcn restrains retinoic acid-orchestrated tissue recruitment and TGF-- mediated programming for TRM differentiation. A genetic interaction screen identified mitochondrial enzymes Me3 and Acss1 as putative targets that orchestrate metabolic adaptation and TRM formation under Flcn-associated lysosomal dysregulation, thereby establishing inter-organelle communication as a driver of this process. Our central hypothesis is that lysosomal signaling nodes integrate nutrient and immunological signals to program long-lived TRM cells, and targeting such signaling nodes is an innovative strategy to enhance the quantity and quality of TRM cells for tissue immunity. Our model represents a major advance in establishing an interplay between nutrients, organelle signaling and immunological pathways that dictates metabolic adaptation and tissue immunity and points to new avenues to improve TRM responses and tissue immunity. Aim 1. Establish the molecular and functional effects of lysosomal signaling nodes in TRM development. Aim 2. Define the intersection of nutrient and immunological signals for TRM differentiation and trafficking. Aim 3. Dissect mechanisms of metabolic and nutrient adaptation for TRM development. Despite the recent interest in immunometabolism, the function and mechanism of nutrient signaling and metabolic adaptation in TRM biology remain poorly understood. Building upon our expertise and innovation that combine T cell biology, mouse genetics, functional genomics and systems biology approaches, we predict our studies will establish a new paradigm by addressing fundamental questions in TRM biology and immunometabolism, with potentials for translation into innovative therapeutic strategies.
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