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Abstract B067: Distinct necessity of mitochondrial complex I and III for regulatory T-cell function

Regulatory T-cells (Treg cells) are major mediators of immunological homeostasis and tolerance, and their actions suppress responses to self-antigens that are aberrant as well as anti-tumor. Recent studies have demonstrated that, relative to other CD4+ T-cell subsets, Treg cells display increased mitochondrial metabolism and the Treg cell lineage-defining transcription factor, FOXP3, promotes respiration. However, it remains unknown whether Treg cells require the mitochondrial respiratory chain for their suppressive capacity, lineage stability, or survival. Our lab recently found that constitutive Treg cell-specific ablation of mitochondrial respiratory chain complex III but not complex I resulted in the development of a fatal inflammatory disease early in life. Treg cells lacking complex III survived and maintained proliferative capacity, but displayed a loss of suppressive function. We found that in adults, tamoxifen induced deletion of mitochondrial complex III or complex I from Treg cells impaired tumorigenesis. Surprisingly, only loss of complex III resulted in the development of fatal inflammatory disease. Because mitochondrial complex I inhibitors are being explored for cancer treatments, we are investigating the mechanism by which loss of complex I activity in Tregs prevents tumorigenesis. Citation Format: Elizabeth M. Steinert, Samuel E. Weinberg, Navdeep S. Chandel. Distinct necessity of mitochondrial complex I and III for regulatory T-cell function [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B067.