Metabolic Reprogramming of Alloreactive T Cells Through TCR/MYC/mTORC1/E2F6 Signaling in aGvHD Patients

Acute graft-versus-host disease (aGvHD) is the most common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and significantly linked with morbidity and mortality. Although much work has been engaged to investigate aGvHD pathogenesis, the understanding of alloreactive...

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Bibliographic Details
Published in:Frontiers in immunology 2022-03, Vol.13, p.850177-850177
Main Authors: Pan, Zengkai, Huang, Aijie, He, Yang, Zhang, Zilu, Jiang, Chuanhe, Wang, Luxiang, Qing, Kai, Zhang, Sujiang, Wang, Jianmin, Hu, Xiaoxia
Format: Article
Language:English
Subjects:
aGvHD
allogeneic hematopoietic stem cell transplantation
glycolytic
Immunology
metabolic reprogramming
T cells
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Summary:Acute graft-versus-host disease (aGvHD) is the most common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and significantly linked with morbidity and mortality. Although much work has been engaged to investigate aGvHD pathogenesis, the understanding of alloreactive T-cell activation remains incomplete. To address this, we studied transcriptional activation of carbohydrate, nucleotide, tricarboxylic acid (TCA) cycle, and amino acid metabolism of T cells before aGvHD onset by mining the Gene Expression Omnibus (GEO) datasets. Glycolysis had the most extensive correlation with other activated metabolic sub-pathways. Through Pearson correlation analyses, we found that glycolytic activation was positively correlated with activated CD4 memory T-cell subset and T-cell proliferation and migration. T-cell receptor (TCR), mechanistic target of rapamycin complex 1 (mTORC1), myelocytomatosis oncogene (MYC) signaling pathways and E2F6 might be "master regulators" of glycolytic activity. aGvHD predictive model constructed by glycolytic genes ( , , and ) through logistic regression showed high predictive and discriminative value. Furthermore, higher expressions of , , and in alloreactive T cells were confirmed in our pre-aGvHD patient cohort. And the predictive value of the aGvHD risk model was also validated. In summary, our study demonstrated that glycolytic activation might play a pivotal function in alloreactive T-cell activation before aGvHD onset and would be the potential target for aGvHD therapy.
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2022.850177