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Review
. 2020 Jul 24:11:1517.
doi: 10.3389/fimmu.2020.01517. eCollection 2020.

V体育安卓版 - Metabolic Pathways in Alloreactive T Cells

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Review

Metabolic Pathways in Alloreactive T Cells (VSports手机版)

Rebecca A Brown et al. Front Immunol. .

Abstract

Allogeneic hematopoietic stem cell transplantation (aHSCT) is a curative therapy for a range of hematologic illnesses including aplastic anemia, sickle cell disease, immunodeficiency, and high-risk leukemia, but the efficacy of aHSCT is often undermined by graft-versus-host disease (GVHD), where T cells from the donor attack and destroy recipient tissues VSports手机版. Given the strong interconnection between T cell metabolism and cellular function, determining the metabolic pathways utilized by alloreactive T cells is fundamental to deepening our understanding of GVHD biology, including its initiation, propagation, and potential mitigation. This review summarizes the metabolic pathways available to alloreactive T cells and highlights key metabolic proteins and pathways linking T cell metabolism to effector function. Our current knowledge of alloreactive T cell metabolism is then explored, showing support for glycolysis, fat oxidation, and glutamine metabolism but also offering a potential explanation for how these presumably contradictory metabolic findings might be reconciled. Examples of additional ways in which metabolism impacts aHSCT are addressed, including the influence of butyrate metabolism on GVHD resolution. Finally, the caveats and challenges of assigning causality using our current metabolic toolbox is discussed, as well as likely future directions in immunometabolism, both to highlight the strengths of the current evidence as well as recognize some of its limitations. .

Keywords: AMPK; GVHD biology; alloreactive T cells; fatty acid oxidation (FAO); glycolysis; immunometabolism; mammalian target of rapamycin (mTOR). V体育安卓版.

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Figures

Figure 1
Figure 1
Alloreactive CD8+ T cells simultaneously increase both OXPHOS and glycolysis. 2 × 106 CD45.1+ B6 T cells and 5 × 106 B6 bone marrow (BM) cells were transplanted into irradiated, allogeneic (B6 × DBA F1) recipients. On day 7 post-transplant, donor CD8+ T cells (CD8+CD45.1+TCR-β+) were flow-sorted and 2 × 105 cells placed into a Seahorse metabolic analyzer. Values for both oxygen consumption rate (OCR) and extracellular acidification of the media (ECAR), a proxy for glycolysis, were simultaneously increased in day 7 CD8+ donor T cells.
Figure 2
Figure 2
Metabolic pathways that distinguish alloreactive and syngeneic T cells. T cells isolated from allogeneic recipients have a unique metabolic profile including a greater increase in both glycolysis and oxidative phosphorylation (OXPHOS) (29, 53, 124). While various carbon sources contribute to this increased oxidative metabolism, including glucose (29, 52) and fatty acids (54), the relative contribution of each substrate remains to be determined. Glutaminolysis and the PPP are also preferentially upregulated in alloreactive T cells, as is activation of the AMPK and mTOR pathways (29, 70, 74). Because T cell metabolism is a dynamic process, this figure represents known or suspected metabolic activity in donor T cells on day 7 post-transplant. The relative contribution of each pathway is likely to change over time as discussed in the text.

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