장정희 (University of Michigan Medical School) | 한빛사논문 > 한빛사

한빛사논문

조회253

University of Michigan Medical School

Proc. Natl. Acad. Sci. USA, Apr 23 2024, 121 (17) | https://doi.org/10.1073/pnas.2318420121 Iron regulates the quiescence of naive CD4 T cells by controlling mitochondria and cellular metabolism

Ajay Kumar^a,1,2, Chenxian Ye^a,1, Afia Nkansah^a,b, Thomas Decoville^a, Garrett M. Fogo^c, Peter Sajjakulnukit^d, Mack B. Reynolds^a, Li Zhang^d, Osbourne Quaye^b, Young- Ah Seo^e, Thomas H. Sanderson^c,f, Costas A. Lyssiotis^d,f,g, and Cheong- Hee Chang^a,2,3

^aDepartment of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109.

^bDepartment of Biochemistry, Cell and Molecular Biology, West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Accra G4522, Ghana.

^cDepartment of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI 48109.

^dRogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109.

^eDepartment of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109.

^fDepartment of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, MI 48109.

^gDepartment of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109.

¹A.K. and C.Y. contributed equally to this work.

²A.K. and C.-H.C. contributed equally to this work.

³To whom correspondence may be addressed. : Cheong-Hee Chang

Abstract

In response to an immune challenge, naive T cells undergo a transition from a quiescent to an activated state acquiring the effector function. Concurrently, these T cells reprogram cellular metabolism, which is regulated by iron. We and others have shown that iron homeostasis controls proliferation and mitochondrial function, but the underlying mechanisms are poorly understood. Given that iron derived from heme makes up a large portion of the cellular iron pool, we investigated iron homeostasis in T cells using mice with a T cell-specific deletion of the heme exporter, FLVCR1 [referred to as knockout (KO)]. Our finding revealed that maintaining heme and iron homeostasis is essential to keep naive T cells in a quiescent state. KO naive CD4 T cells exhibited an iron-overloaded phenotype, with increased spontaneous proliferation and hyperactive mitochondria. This was evidenced by reduced IL-7R and IL-15R levels but increased CD5 and Nur77 expression. Upon activation, however, KO CD4 T cells have defects in proliferation, IL-2 production, and mitochondrial functions. Iron-overloaded CD4 T cells failed to induce mitochondrial iron and exhibited more fragmented mitochondria after activation, making them susceptible to ferroptosis. Iron overload also led to inefficient glycolysis and glutaminolysis but heightened activity in the hexosamine biosynthetic pathway. Overall, these findings highlight the essential role of iron in controlling mitochondrial function and cellular metabolism in naive CD4 T cells, critical for maintaining their quiescent state.

논문정보

형식Research article
게재일2024년 04월 (BRIC 등록일 2024-04-18)
연구진국외 연구진
분야 의약학 > 면역의학

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