细胞生物学
脂质代谢
生物
线粒体
新陈代谢
效应器
细胞
生物化学
脂肪酸代谢
功能(生物学)
免疫系统
化学
遗传学
作者
KayLee K. Steiner,Arissa Young,Andrew R. Patterson,Erin Q. Jennings,Channing Chi,Zaid Hatem,Darren R. Heintzman,Ayaka Sugiura,Emily N. Arner,Allison E. Sewell,Matthew Z. Madden,Richmond Okparaugo,Emilia V Fallman,Katherine N. Gibson‐Corley,Kelsey Voss,Denis A. Mogilenko,Jeffrey C. Rathmell
标识
DOI:10.1101/2024.07.08.602554
摘要
Lipid metabolism is fundamental to CD4+ T cell metabolism yet remains poorly understood across subsets. Therefore, we performed targeted in vivo CRISPR/Cas9 screens to identify lipid-associated genes essential for T cell subset functions. These screens established mitochondrial fatty acid synthesis (mtFAS) genes Mecr, Mcat and Oxsm as highly impactful. Of these, the inborn error of metabolism gene Mecr was most dynamically regulated. Effector and memory T cells were reduced in Mecrfl/fl; Cd4cre mice, and MECR was required for activated CD4+ T cells to efficiently proliferate, differentiate, and survive. Mecr-deficient T cells also had decreased mitochondrial respiration, reduced TCA intermediates, and accumulated intracellular iron, which contributed to cell death and sensitivity to ferroptosis. Importantly, Mecr-deficient T cells exhibited fitness disadvantages in inflammatory, tumor, and infection models. mtFAS and MECR thus play important roles in activated T cells and may provide targets to modulate immune functions in inflammatory diseases. The immunological state of MECR- and mtFAS-deficient patients may also be compromised.
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