Distinct modes of mitochondrial metabolism uncouple T cell differentiation and function

Will Bailis, Justin A. Shyer, Jun Zhao, Juan Carlos Garcia Canaveras, Fatimah J. Al Khazal, Rihao Qu, Holly R. Steach, Piotr Bielecki, Omair Khan, Ruaidhri Jackson, Yuval Kluger, Louis J. Maher, Joshua Rabinowitz, Joe Craft () and Richard A. Flavell ()
Additional contact information
Will Bailis: Yale School of Medicine
Justin A. Shyer: Yale School of Medicine
Jun Zhao: Yale School of Medicine
Juan Carlos Garcia Canaveras: Princeton University
Fatimah J. Al Khazal: Mayo Clinic College of Medicine and Science
Rihao Qu: Yale School of Medicine
Holly R. Steach: Yale School of Medicine
Piotr Bielecki: Yale School of Medicine
Omair Khan: Yale School of Medicine
Ruaidhri Jackson: Yale School of Medicine
Yuval Kluger: Yale School of Medicine
Louis J. Maher: Mayo Clinic College of Medicine and Science
Joshua Rabinowitz: Princeton University
Joe Craft: Yale School of Medicine
Richard A. Flavell: Yale School of Medicine

Nature, 2019, vol. 571, issue 7765, 403-407

Abstract: Abstract Activated CD4 T cells proliferate rapidly and remodel epigenetically before exiting the cell cycle and engaging acquired effector functions. Metabolic reprogramming from the naive state is required throughout these phases of activation1. In CD4 T cells, T-cell-receptor ligation—along with co-stimulatory and cytokine signals—induces a glycolytic anabolic program that is required for biomass generation, rapid proliferation and effector function2. CD4 T cell differentiation (proliferation and epigenetic remodelling) and function are orchestrated coordinately by signal transduction and transcriptional remodelling. However, it remains unclear whether these processes are regulated independently of one another by cellular biochemical composition. Here we demonstrate that distinct modes of mitochondrial metabolism support differentiation and effector functions of mouse T helper 1 (TH1) cells by biochemically uncoupling these two processes. We find that the tricarboxylic acid cycle is required for the terminal effector function of TH1 cells through succinate dehydrogenase (complex II), but that the activity of succinate dehydrogenase suppresses TH1 cell proliferation and histone acetylation. By contrast, we show that complex I of the electron transport chain, the malate–aspartate shuttle and mitochondrial citrate export are required to maintain synthesis of aspartate, which is necessary for the proliferation of T helper cells. Furthermore, we find that mitochondrial citrate export and the malate–aspartate shuttle promote histone acetylation, and specifically regulate the expression of genes involved in T cell activation. Combining genetic, pharmacological and metabolomics approaches, we demonstrate that the differentiation and terminal effector functions of T helper cells are biochemically uncoupled. These findings support a model in which the malate–aspartate shuttle, mitochondrial citrate export and complex I supply the substrates needed for proliferation and epigenetic remodelling early during T cell activation, whereas complex II consumes the substrates of these pathways, which antagonizes differentiation and enforces terminal effector function. Our data suggest that transcriptional programming acts together with a parallel biochemical network to enforce cell state.

Date: 2019
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-019-1311-3 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:571:y:2019:i:7765:d:10.1038_s41586-019-1311-3

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-019-1311-3

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().