Metabolic reprogramming of alloantigen-activated T cells after hematopoietic cell transplantation
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
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
View: Text | PDF
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

×

Figure 2

T cells undergo metabolic reprogramming in response to alloantigens after BMT.

Options: View larger image (or click on image) Download as PowerPoint
T cells undergo metabolic reprogramming in response to alloantigens afte...
T cells were isolated from allogeneic BALB/c and syngeneic B6 recipient spleens at indicated times after BMT and measured for intracellular metabolites by mass spectrometry. (A) The heat map represents the log2 value of the relative amount of each metabolite, which is grouped in the indicated metabolic pathway. (B) The glycolytic pathway is elucidated and the key metabolites measured are highlighted in red. (C) The mRNA expression of the metabolic genes of glycolytic pathway was determined by qPCR on the donor T cells from allogeneic or syngeneic recipients at 14 days after BMT. The relative level of mRNA is based on the resting T cells as 1. (D) The glucose uptake activity and GLUT1 expression in donor T cells from allogeneic or syngeneic recipients were determined by flow cytometry. Data are shown as mean ± SD (A and B, n = 6; C, n = 3; D, n = 7–10). *P < 0.05, ***P < 0.001, 2-tailed Student t test (D). The metabolite expression profile and the input gene list are provided in Supplemental Tables 1–3 and Supplemental Table 4, respectively.