Metabolism inhibitors, in concert with malignancy immunotherapies, spotlight an avenue by which to achieve better antitumor efficacy and functional tolerance to allografts. important metabolic pathways involved in alloantigen-activated T cells and to discuss how manipulating these pathways can serve as potential new therapeutic strategies to induce immune tolerance after allo-transplantation. We will also summarize the recent progress in regulating T-cell metabolism in bone marrow transplantation by targeting novel metabolic regulators or immune checkpoint molecules. -ketoglutarate (-KG) through the process of glutaminolysis (16, 17). Metabolism and CD4+T Cell Differentiation Depending on the nature of antigen and cytokine transmission, CD4+ A 438079 hydrochloride T cells differentiate into Th1, Th2, Th9, Th17, T follicular helper cells (Tfh), Tr-1, or Treg. While Th1, Th2, and Th17 are pathogenic, Tr-1 and Treg are suppressive in acute GVHD (18C20). Metabolism plays a critical role in CD4+ T-cell differentiation (12). While Th1, Th2, and Th17 lineages preferentially use glycolysis to meet dynamic demand though activation of PI3K/Akt/mTOR pathway, CD4+ Tregs use mitochondrial-dependent FAO (4). Therefore, enhanced FAO inhibiting mTOR prospects to increased Treg generation (21). Hypoxia-inducible factor 1 is the important regulator of anabolic metabolism in Th17?cells (22). In the mean time, Tfh, a pathogenic T-cell subset in chronic GVHD, depend on glycolysis and lipogenesis to meet energy demands required for differentiation (23). The A 438079 hydrochloride metabolic profiles of Th9 and Tr1 remain unclear. Metabolism of Allogeneic T Cells Glucose Metabolism Using MHC-mismatched or haploidentical murine models of BMT, we uncovered that upon alloantigen activation, donor T cells increase both glycolysis and OXPHOS to obtain dynamic materials necessary for activation and proliferation (2, 9). Albeit, they preferentially rely on glycolysis to maintain their capacity to induce GVHD A 438079 hydrochloride (2, 9, 24). While OXPHOS of donor T cells isolated from syngeneic (no GVHD) and allogeneic (GVHD) recipients were similar, the glycolytic activity of donor T cells was significantly higher in allogeneic than syngeneic recipients, indicating an escalation of T-cell glucose metabolism correlated with Rabbit Polyclonal to STK24 GVHD development A 438079 hydrochloride (2) (Physique ?(Figure1).1). Furthermore, T cells isolated from livers of allogeneic recipients exhibited higher glycolytic activity compared to those of syngeneic recipients 14?days after allo-HCT, implying an enduring glycolytic response by allogeneic T cells in GVHD target organs. While activated T cells upregulate and maintain expression of Glut1 for sufficient glucose uptake (17), allo-activated T cells also increase Glut 3 to fulfill their extremely high demand for glucose (2). In addition, alloantigen-activated T cells upregulate both hexokinase 1 (HK1) and HK2 to facilitate induction of glycolysis (2). To maintain sufficient glycolytic activity, allogeneic CD4+ T cells activate mTOR and increase differentiation into Th1 and Th17 (2, 25) while decreasing Treg generation (24). Inhibition of glycolysis by genetic depletion or pharmacological blockade of mTORC1 (2, 26) or glycolytic checkpoints, including glut-1 (24), HK-2, PFKB3 (2), or PKM2 (unpublished study), reduces alloreactive T-cell generation and subsequently ameliorates GVHD severity. Alternatively, enhancing FAO to inhibit mTOR using PI3K/AKT or AMPK inhibitors (27, 28) effectively prevents GVHD development. Open in a separate window Physique 1 (A) Na?ve/resting T cells are dependent on oxidative phosphorylation with fatty acid oxidation (FAO) as a major material resource. Upon activation by self-antigens under homeostatic state, na?ve/resting T cells reprogram their metabolic phenotype to become partially A 438079 hydrochloride activated T cells (29), which possess glycolytic metabolic phenotype. Due to lack of specific TCR stimulation, a large proportion of non-alloreactive T cells gradually pass away. However, specific self-epitopes of T cells can become memory T cells (Tm) which depend upon FAO for their metabolism. (B) Upon activation by alloantigen in transplant recipients, na?ve/resting T cells proliferate and their memory differentiate to trigger T cells both alloreactive and.