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 6

Ablation of mTOR or RAPTOR, not RICTOR, leads to a significant reduction in Th1 but enhancement in iTreg differentiation.

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Ablation of mTOR or RAPTOR, not RICTOR, leads to a significant reduction...
Lethally irradiated BALB/c mice were transplanted with TCD-BM from B6 Ly5.1 donors alone or with CD25-depleted T cells at 1 × 106/mouse from WT or KO donors on B6 background. After 14 days, recipient mice were euthanized and blood, spleen, and livers were harvested. (A and B) Absolute numbers of donor H-2Kb+Ly5.1–CD4+ or H-2Kb+Ly5.1–CD8+ T cells in recipient liver (A) and spleen (B) are displayed. Summary of CXCR3 expression gated on H-2Kb+Ly5.1–CD4+ or CD8+ T cells in the spleens are shown. (C) The percentages of IFN-γ– and IL-4/5–secreting cells from spleen or liver are shown in gated H-2Kb+Ly5.1–CD4+ or H-2Kb+Ly5.1–CD8+ T cells. (D and E) Total numbers of IFN-γ– or IL-4/5–secreting cells are shown on CD4+ or CD8+ donor T cells in recipient liver (D) or spleen (E). (F) The expression of CD25 and FOXP3 gated on donor CD4+ spleen cells. (G)Absolute number of iTregs among donor T cells. Data are pooled from three independent experiments with 15 mice per group (mean ± SEM), *P < 0.05; **P < 0.01; ***P < 0.001, two-tailed Student t test (A, B, D, E, and G).