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
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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 4

Delayed rapamycin treatment reduces GVHD through decreasing glycolytic activity in donor T cells.

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Delayed rapamycin treatment reduces GVHD through decreasing glycolytic a...
(A and B) Relative levels of Raptor and Rictor mRNA (A), and pS6 expression (B) are shown in T cells from allogeneic BALB/c and syngeneic B6 recipients at 14 days after BMT (C–H) Lethally irradiated BALB/c mice were transplanted with 5 × 106/mouse TCD-BM from B6 Ly5.1 mice plus 1 × 106/mouse T cells isolated from B6 donors. Recipients were administrated daily i.p. with rapamycin (1.5 mg/kg) or 0.5% methylcellulose (vehicle) started from day 7 until day 14 after BMT. (C) The GVHD clinical score monitored through experiment and the pathological score of GVHD target organs at the day 14 after BMT are shown. (D) The levels of serum cytokines are displayed. (E) Absolute numbers of donor H-2Kb+Ly5.1–CD4+ or CD8+ T cells in recipient liver and spleen are depicted. (F) The bar graphs show ECAR and OCR values of spleens T cells or liver monocytes. (G) The expression of GLUT1 and glucose uptake are shown on the spleen T cells (Supplemental Figure 4A). Data are representative of two independent experiments with 5–7 mice per group. Error bars show mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, two-tailed Student t test (A, B, right panel of C, and D–G), and Mann-Whitney U test (C, left panel). (H) The heat map represents the log2 value of the relative individual mRNA expression of glycolytic enzymes in splenic T cells. The input gene list and expression profile are provided in Supplemental Table 5. Data are representative of two independent experiments (n = 3). S.I., small intestine; L.I., large intestine.