Mitochondrial Fatty Acid Synthesis and MECR Regulate CD4+ T Cell Function and Oxidative Metabolism

Imbalanced effector and regulatory CD4+ T cell subsets drive many inflammatory diseases. These T cell subsets rely on distinct metabolic programs, modulation of which differentially affects T cell fate and function. Lipid metabolism is fundamental to CD4+ T cell metabolism yet remains poorly understood across these subsets. Therefore, we performed targeted in vivo CRISPR/Cas9 screens to identify lipid metabolism genes and pathways essential for T cell functions. These screens established mitochondrial fatty acid synthesis (mtFAS) genes Mecr, Mcat and Oxsm as key metabolic regulators. Of these, the inborn error of metabolism gene Mecr was most dynamically regulated. Mecrfl/fl; Cd4cre mice had normal naïve CD4+ and CD8+ T cell numbers, demonstrating MECR is not essential in homeostatic conditions. However, effector and memory T cells were reduced in Mecr-KO and the function of MECR promoted CD4+ T cell prolifferation, differentiate, and survive. Interestingly, T cells ultimately showed increased mTORC1 activity and signs of mitochondrial stress in the absence of MECR. Mecr-deficient T cells also had decreased mitochondrial respiration, reduced TCA intermediates, and accumulated intracellular iron, which contributed to increased cell death and sensitivity to ferroptosis. Importantly, MECR-deficient T cells exhibited fitness disadvantages in in vivo inflammatory, tumor, and infection models and were less effective at driving disease in a model of IBD. Thus, mtFAS and MECR play an important role in activated T cells and may be a target to modulate immunological function in inflammatory diseases. These findings may also provide insight to the immunological state of MECR- and other mtFAS-deficient patients. Mecr fl/fl/ Cd4 cre - or Mecr fl/fl/ Cd4 cre + naïve T cells were transferred into Rag1-/- mice to develop Inflammatory Bowel Disease. After disease development, CD4+ T cells were isolated from the spleens of Rag1-/- mice and subjected to RNA isolation.