Life Sciences Seminar: T Cell Immunometabolism in Function and Disease

Life Sciences Seminar
T Cell Immunometabolism in Function and Disease

KayLee Steiner (Biotechnology ’20)
Cancer Biology PhD Candidate in the Jeff Rathmell Lab at Vanderbilt University Department of Pathology, Microbiology, and Immunology

Abstract:
Inflammatory diseases are often driven by imbalanced proinflammatory effector and anti-inflammatory regulatory CD4 T helper cells (Th cells). These T cell subsets rely on distinct metabolic programs, modulation of which can affect Th cell differentiation and disease development. Here multiple in vivo CRISPR/Cas9 screens of lipid metabolic genes identified the mitochondrial fatty acid synthesis (mtFAS) pathway as critical for the fitness and function of proinflammatory Th cells . Mecr was found to be significantly depleted in models of Inflammatory Bowel Disease (IBD), lLung iInflammation (CD4) and adoptive cell transfer tumor therapy (CD8) along with other mtFAS genes Mcat and Oxsm. We focused on Mecr, which is associated with an inborn error of metabolism and is the rate limiting enzyme in this pathway to generate mitochondrial lipoic acid. Surprisingly, despite being a hit in the CRISPR screen, we found that that Mecr was not essential. Mecrfl/fl; Cd4cre KO mice had normal thymic development and naïve CD4 and CD8 T cell numbers. Effector and memory cells were, however, reduced in the periphery and Mecr was required for activated CD4 T cells to efficiently proliferate, differentiate, and survival, and differentiate. Th1 cell differentiation was specifically decreased, and T cells showed decreased mTORC1 activity and signs of mitochondrial stress in the absence of Mecr . Consistent with a requirement for lipoic acid synthesis for pyruvate dehydrogenase and ETC complex metabolism, Mecr-KO cells showed decreased mitochondrial respiration and ETC proteins. Interestingly, Mecr-deficient T cells accumulated intracellular iron, which contributed to cell death. Mecr-deficient T cells had reduced fitness and Th1 function in a model of IBD, with reduced Tbet and IFNγ. Together, these results show that mtFAS and Mecr play important roles in T cell immunometabolism and may provide targets to modulate immunological function in inflammatory diseases or Mecr-deficient patients.

Intended Audience:
Beginners, undergraduates, graduates, experts. Those with interest in the topic.

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