Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity

Xu, Ke; Yin, Na; Peng, Min; Stamatiades, Efstathios G.; Shyu, Amy; Li, Peng; Zhang, Xian; Mytrang, H.; Wang, Zhaoquan; Capistrano, Kristelle J.; Chou, Chun; Levine, Andrew G.; Rudensky, Alexander Y.; Li, Ming O.

doi:10.1126/science.abb2683

Cited by 214 publications

(158 citation statements)

References 31 publications

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“…Multiple pathways related to DCBLD2 were implicated in immunological function. For instance, inhibition of PI3K-dependent phosphorylation of Akt and its transcription factor target Foxo1 resulted in defective T cell immunity (Xu et al, 2021). Hippo signaling pathway was also involved in T cell immunity (Bouchard et al, 2020) and TGF-beta signaling pathway were known to induce M2-like macrophage polarization (Gratchev, 2017).…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Profiling Identifies DCBLD2 as a Diagnostic and Prognostic Biomarker in Pancreatic Ductal Adenocarcinoma

Feng

et al. 2021

Front. Mol. Biosci.

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Background: Accumulating evidence shows that the elevated expression of DCBLD2 (discoidin, CUB and LCCL domain-containing protein 2) is associated with unfavorable prognosis of various cancers. However, the correlation of DCBLD2 expression value with the diagnosis and prognosis of pancreatic ductal adenocarcinoma (PDAC) has not yet been elucidated. Methods: Univariate Cox regression analysis was used to screen robust survival-related genes. Expression pattern of selected genes was investigated in PDAC tissues and normal tissues from multiple cohorts. Kaplan–Meier (K–M) survival curves, ROC curves and calibration curves were employed to assess prognostic performance. The relationship between DCBLD2 expression and immune cell infiltrates was conducted by CIBERSORT software. Biological processes and KEGG pathway enrichment analyses were adopted to clarify the potential function of DCBLD2 in PDAC. Results: Univariate analysis, K–M survival curves and calibration curves indicated that DCBLD2 was a robust prognostic factor for PDAC with cross-cohort compatibility. Upregulation of DCBLD2 was observed in dissected PDAC tissues as well as extracellular vesicles from both plasma and serum samples of PDAC patients. Both DCBLD2 expression in tissue and extracellular vesicles had significant diagnostic value. Besides, DCBLD2 expression was correlated with infiltrating level of CD8+ T cells and macrophage M2 cells. Functional enrichment revealed that DCBLD2 might be involved in cell motility, angiogenesis, and cancer-associated pathways. Conclusion: Our study systematically analyzed the potential diagnostic, prognostic and therapeutic value of DCBLD2 in PDAC. All the findings indicated that DCBLD2 might play a considerably oncogenic role in PDAC with diagnostic, prognostic and therapeutic potential. These preliminary results of bioinformatics analyses need to be further validated in more prospective studies.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic Profiling Identifies DCBLD2 as a Diagnostic and Prognostic Biomarker in Pancreatic Ductal Adenocarcinoma

Feng

et al. 2021

Front. Mol. Biosci.

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“…T cells have been shown to rapidly upregulate aerobic glycolysis in response to T cell receptor (TCR) and coreceptor ligation ( Frauwirth et al, 2002 ; Menk et al, 2018 ; Xu et al, 2021 ). Although early NK cell responses to MCMV infection are dependent on activation of pro-inflammatory cytokines (e.g., IL-12, IL-18, and type I IFNs; Madera and Sun, 2015 ; Sun et al, 2012 ), NK cells can also sense MCMV-infected cells via ligation of their activating receptor Ly49H to the virally encoded glycoprotein m157 ( Arase et al, 2002 ; Brown et al, 2001 ; Daniels et al, 2001 ; Smith et al, 2002 ; Sun et al, 2009 ).…”

Section: Resultsmentioning

confidence: 99%

“…Taken together, these findings suggest that stimulation through proinflammatory cytokines alone can promote increases in the glycolytic capacity of NK cells. Thus, during viral infection, the glycolytic rate of NK cells is upregulated by the initial cytokine surge, but then returns to basal levels after 7 days, whereas glycolysis in anti-viral CD8 + T cells peaks later, likely due to control of Ldha expression by TCR ligation rather than cytokines ( Xu et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Lactate dehydrogenase A-dependent aerobic glycolysis promotes natural killer cell anti-viral and anti-tumor function

et al. 2021

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SUMMARY Natural killer (NK) cells are cytotoxic lymphocytes capable of rapid cytotoxicity, cytokine secretion, and clonal expansion. To sustain such energetically demanding processes, NK cells must increase their metabolic capacity upon activation. However, little is known about the metabolic requirements specific to NK cells in vivo . To gain greater insight, we investigated the role of aerobic glycolysis in NK cell function and demonstrate that their glycolytic rate increases rapidly following viral infection and inflammation, prior to that of CD8 + T cells. NK cell-specific deletion of lactate dehydrogenase A (LDHA) reveals that activated NK cells rely on this enzyme for both effector function and clonal proliferation, with the latter being shared with T cells. As a result, LDHA-deficient NK cells are defective in their anti-viral and anti-tumor protection. These findings suggest that aerobic glycolysis is a hallmark of NK cell activation that is key to their function.

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“…Further, activated CD8 + T cells exposed to the short-chain fatty acid (SCFA) butyrate display elevated FoxO1 expression and memory potential (Bachem et al 2019). Additionally, mitochondrial respiration supports Akt-FoxO1 signaling (Xu et al 2021). Thus, mTOR signaling and metabolic reprogramming may contribute to memory fate differentiation at the first cell division and later at the effector stage.…”

Section: Metabolic Control Of Memory T Cellsmentioning

confidence: 99%

Metabolic Control of Memory T-Cell Generation and Stemness

Raynor

Chapman

Chi

2021

Cold Spring Harb Perspect Biol

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The formation of long-lived memory T cells is a critical feature of the adaptive immune response. T cells undergo metabolic reprogramming to establish a functional memory population. While initial studies characterized key metabolic pathways necessary for memory T-cell development, recent findings highlight that metabolic regulation of memory T-cell subsets is diverse. Here we describe the different requirements for metabolic programs and metabolism-related signaling pathways in memory T-cell development. We further discuss the contribution of cellular metabolism to memory T-cell functional reprogramming and stemness within acute and chronic inflammatory environments. Last, we highlight knowledge gaps and propose approaches to determine the roles of metabolites and metabolic enzymes in memory T-cell fate. Understanding how cellular metabolism regulates a functionally diverse memory population will undoubtedly provide new therapeutic insights to modulate protective T-cell immunity in human disease.

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Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity

Cited by 214 publications

References 31 publications

Transcriptomic Profiling Identifies DCBLD2 as a Diagnostic and Prognostic Biomarker in Pancreatic Ductal Adenocarcinoma

Transcriptomic Profiling Identifies DCBLD2 as a Diagnostic and Prognostic Biomarker in Pancreatic Ductal Adenocarcinoma

Lactate dehydrogenase A-dependent aerobic glycolysis promotes natural killer cell anti-viral and anti-tumor function

Metabolic Control of Memory T-Cell Generation and Stemness

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