Metabolic reprogramming of alloantigen-activated T cells after hematopoietic cell transplantation
Hung D. Nguyen, … , Shikhar Mehrotra, Xue-Zhong Yu
Hung D. Nguyen, … , Shikhar Mehrotra, Xue-Zhong Yu
Published March 7, 2016
Citation Information: J Clin Invest. 2016;126(4):1337-1352. https://doi.org/10.1172/JCI82587.
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Research Article Immunology

Metabolic reprogramming of alloantigen-activated T cells after hematopoietic cell transplantation

Abstract

Alloreactive donor T cells are the driving force in the induction of graft-versus-host disease (GVHD), yet little is known about T cell metabolism in response to alloantigens after hematopoietic cell transplantation (HCT). Here, we have demonstrated that donor T cells undergo metabolic reprograming after allogeneic HCT. Specifically, we employed a murine allogeneic BM transplant model and determined that T cells switch from fatty acid β-oxidation (FAO) and pyruvate oxidation via the tricarboxylic (TCA) cycle to aerobic glycolysis, thereby increasing dependence upon glutaminolysis and the pentose phosphate pathway. Glycolysis was required for optimal function of alloantigen-activated T cells and induction of GVHD, as inhibition of glycolysis by targeting mTORC1 or 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) ameliorated GVHD mortality and morbidity. Together, our results indicate that donor T cells use glycolysis as the predominant metabolic process after allogeneic HCT and suggest that glycolysis has potential as a therapeutic target for the control of GVHD.

Authors

Hung D. Nguyen, Shilpak Chatterjee, Kelley M.K. Haarberg, Yongxia Wu, David Bastian, Jessica Heinrichs, Jianing Fu, Anusara Daenthanasanmak, Steven Schutt, Sharad Shrestha, Chen Liu, Honglin Wang, Hongbo Chi, Shikhar Mehrotra, Xue-Zhong Yu

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Figure 7

Glycolysis is required for T cell activation and proliferation in response to alloantigens after BMT.

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Glycolysis is required for T cell activation and proliferation in respon...
Lethally irradiated BALB/c mice were transplanted with 1.5 × 106 CFSE-labeled T cells from B6 donors and administrated i.p. with 2-DG (1 g/kg, twice a day), DHEA (100 mg/kg, twice a day), or Eto (35 mg/kg, twice a day). Four days later, splenocytes were subjected to surface CD4+, CD8+, and H-2Kb staining, as well as intracellular flow cytometric staining for IFN-γ. (A) T cell proliferation and activation was determined as CFSE dilution and IFN-γ secretion. (B and C) Absolute numbers of H-2Kb+ donor T cells (B) and IFN-γ secreting donor T cells (C) in recipient spleens. (D) Profile of donor T cell proliferation reflected by CFSE dilution. (E) Summary of donor T cell proliferation reflected by %CFSE diluted cells. The data are representative of two independent experiments with at least 4 mice per group in each experiment. Data show mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, two-tailed Student t test (B, D, and E).