Metabolic control of regulatory T cells during metabolic stress caused by viral pneumonia

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PROJECT SUMMARY Regulatory T (Treg) cells are a subset of CD4+ T cells that maintain immune self-tolerance and mediate recovery from viral pneumonia by resolving lung inflammation and orchestrating tissue repair after lung injury. Treg cells also display metabolic plasticity; they modulate which substrates they acquire and how they metabolize them to support their functions in metabolically stressful microenvironments. AMP-activated Protein Kinase (AMPK) serves as a master regulator metabolic homeostasis by inducing energy-replenishing processes during energetic stress. AMPK promotes mitochondrial biogenesis (via epigenetic induction of the mitochondrial mass-promoting molecule PGC-1α) and long-chain fatty acid oxidation (LC-FAO, via activation of the mitochondrial LC-FA importer CPT1) in states of energy depletion. Treg cells have high levels of AMPK, and pharmacologic activation of AMPK induces Treg cell generation in vitro and in mouse models of lung disease. Surprisingly, Treg cell- specific loss of AMPK in vivo does not lead to spontaneous lethal autoimmunity or other signs of Treg cell dys- function, suggesting that AMPK is redundant in Treg cells at homeostatic conditions. To explore the role of AMPK in the Treg cell response to pathologies associated with metabolic stress (nutrient depletion, hypoxia, and oxidative stress), we bred Treg cell-specific AMPK knockout (Treg AMPK KO) mice and challenged them with either intratracheal instillation of influenza virus or subcutaneous engraftment of B16 melanoma tumors. While influenza virus-inoculated Treg AMPK KO mice had lower survival, tumors of Treg AMPK KO mice exhibited impaired growth and smaller volumes relative to controls. These results suggest that AMPK-deficient Treg cells undergo loss-of-function in settings of pathology-induced metabolic stress. Therefore, we hypothesize that Treg cell AMPK-mediated induction of mitochondrial mass and LC-FA oxidation are required for their pro-recovery function during influenza pneumonia. To elucidate the causal mechanisms through which AMPK promotes Treg cell pro-recovery function in the injured lung, we will leverage mice with Treg cell-specific deficiency of either AMPK and CPT1, along with influenza virus infection as a murine model of viral pneumonia. Our Specific Aims are to determine 1) whether AMPK promotes Treg cell pro-recovery function following influenza pneumonia by creating a permissive DNA hypomethylation landscape at Ppargc1a (encodes PGC-1α) to sustain their mitochondrial mass, and 2) whether AMPK-dependent mitochondrial import of LC-FAs is required for Treg cell pro-recovery function following influenza pneumonia. The PI's excellent mentorship network consists of experienced scientists in the fields of immunology, epigenetics, metabolism, and lung disease, all of whom will provide both day-to-day and high-level support during the funding period. The PI's environment is outstanding, with all necessary facilities, equipment, and expertise to complete the research strategy and training plan.