The CD28 Signaling Pathway Regulates Glucose Metabolism

Frauwirth, Kenneth A.; Riley, James L.; Harris, Marian H.; Parry, Richard V.; Rathmell, Jeffrey C.; Plas, David R.; Elstrom, Rebecca; June, Carl H.; Thompson, Craig B.

doi:10.1016/s1074-7613(02)00323-0

Cited by 1,268 publications

(1,240 citation statements)

References 51 publications

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“…This strongly suggests that the increased electron transfer capacity upon differentiation implies a higher utilization of mitochondria for ATP synthesis. Interestingly, the activation process of T lymphocytes through CD28 signalling has been described to be associated mainly to enhanced glycolysis, with only a small proportion of glucose oxidized in mitochondria (Frauwirth et al, 2002). From these results it can be argued that cell differentiation and activation, which are definitely distinct processes, might exhibit different metabolic state.…”

Section: Resultsmentioning

confidence: 96%

An active mitochondrial biogenesis occurs during dendritic cell differentiation

Zaccagnino

Saltarella

Maiorano

et al. 2012

The International Journal of Biochemistry & Cell Biology

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This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. b s t r a c tDendritic cells (DC) are sentinels of the immune system deriving from circulating monocyte precursors recruited to sites of inflammation. In a previous report (Del Prete et al., 2008) we showed that, after differentiation, DC exhibited increased number of condensed mitochondria and dynamic changes in their energy metabolism. A study is presented here showing that the DC differentiation process is characterized by increased expression level and activity of mitochondrial respiratory complexes, as well as by an increased mitochondrial DNA (mtDNA) copy number. Moreover, DC are equipped with more efficient antioxidant protection systems, over expressed most likely to detoxify increased ROS production, as a consequence of the much higher mitochondrial activity. Kinetic analysis of the three main mitochondrial biogenesis-associated genes revealed that the peak in PPAR␥ coactivator-1alpha (PGC-1␣) gene expression was suddenly reached few hours after the onset of the differentiation. While PGC-1␣ expression rapidly declines, the mitochondrial transcription factor A (TFAM) and nuclear respiratory factor-1 (NRF-1) expression gradually increased. These findings demonstrate that an active mitochondrial biogenesis occurs during DC differentiation and further suggest that an early input by the master regulator of mitochondrial biogenesis PGC-1␣ is needed to trigger the subsequent activation of the downstream transcription factors, NRF-1 and TFAM in this process.

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Section: Resultsmentioning

confidence: 96%

An active mitochondrial biogenesis occurs during dendritic cell differentiation

Zaccagnino

Saltarella

Maiorano

et al. 2012

The International Journal of Biochemistry & Cell Biology

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“…40 Activated T cells change their metabolic state by utilizing aerobic glycolysis. [41][42][43] The high rate of glycolysis in activated T cells bypasses the normal oxidation of pyruvate in the mitochondria, resulting in lactic acid fermentation, whereas minimal lactic acid production occurs in resting cells. 44 In our study, we show that CD3/CD28-activated T cells from mouse spleen exhibited significant resistance to apoptosis compared with their naïve/resting counterparts, suggesting that heightened glycolysis as reported in activated cells, and observed in the S49 (OS 4-25) cells, can have a key role in the cell death program.…”

Section: Discussionmentioning

confidence: 99%

T-cell development of resistance to apoptosis is driven by a metabolic shift in carbon source and altered activation of death pathways

et al. 2015

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We developed a model system to investigate apoptotic resistance in T cells using osmotic stress (OS) to drive selection of deathresistant cells. Exposure of S49 (Neo) T cells to multiple rounds of OS followed by recovery of surviving cells resulted in the selection of a population of T cells (S49 ) that failed to die in response to a variety of intrinsic apoptotic stimuli including acute OS, but remained sensitive to extrinsic apoptotic initiators. Genome-wide microarray analysis comparing the S49 (OS 4-25) with the parent S49 (Neo) cells revealed over 8500 differentially regulated genes, with almost 90% of those identified being repressed. Surprisingly, our data revealed that apoptotic resistance is not associated with expected changes in pro-or antiapoptotic Bcl-2 family member genes. Rather, these cells lack several characteristics associated with the initial signaling or activation of the intrinsic apoptosis pathway, including failure to increase mitochondrial-derived reactive oxygen species, failure to increase intracellular calcium, failure to deplete glutathione, failure to release cytochrome c from the mitochondria, along with a lack of induced caspase activity. The S49 (OS 4-25) cells exhibit metabolic characteristics indicative of the Warburg effect, and, despite numerous changes in mitochondria gene expression, the mitochondria have a normal metabolic capacity. Interestingly, the S49 (OS 4-25) cells have developed a complete dependence on glucose for survival, and glucose withdrawal results in cell death with many of the essential characteristics of apoptosis. Furthermore, we show that other dietary sugars such as galactose support the viability of the S49 (OS 4-25) cells in the absence of glucose; however, this carbon source sensitizes these cells to die. Our findings suggest that carbon substrate reprogramming for energy production in the S49 (OS 4-25) cells results in stimulusspecific recognition defects in the activation of intrinsic apoptotic pathways.

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“…Myristoylation of Akt causes its association with the plasma membrane, resulting in its constitutive activation. In vitro, mAkt has been shown to prevent cell death-by-neglect and to increase glycolytic metabolism [25,34,35], possibly through its action on Glut1 expression and cell surface localization [22]. HA-tagged mAkt was cloned into an expression vector driven by a 3.1-kb segment that includes both proximal and distal elements of the of lck promoter [36] and the CD2 enhancer.…”

Section: Generation and Expression Of Makt Transgenementioning

confidence: 99%

“…One role CD28 costimulation plays in T cell activation is to promote rapid up-regulation of glycolysis [25]. Because CD28 activates Akt, the dependence of mAkt-transgenic T cells on CD28 for growth and proliferation was examined (Fig.…”

Section: Akt Promotes Cd28-independent T Cell Growth Proliferation mentioning

confidence: 99%

“…Mitogenic TCR signals with CD28-mediated costimulation cause T cells to induce expression of Glut1, increase rates of glycolysis, and grow rapidly. These events are dependent on CD28 signal transduction because in the absence of CD28-mediated costimulation, Glut1 is poorly induced and T cells fail to increase glycolysis and proliferate [25]. To analyze expression and activity of the mAkt transgene, lysates from two million thymocytes or purified peripheral T cells from nontransgenic (Non) or mAkt-transgenic (Tg) mice were loaded per lane and subjected to SDS-PAGE.…”

Section: Introductionmentioning

confidence: 99%

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Activated Akt promotes increased resting T cell size, CD28‐independent T cell growth, and development of autoimmunity and lymphoma

et al. 2003

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The mechanisms that regulate basal T cell size and metabolic activity are uncertain. Since the phosphatidylinositol-3 phosphate kinase (PI3 K) and Akt (PKB) pathway has been shown in model organisms to regulate both cell size and metabolism, we generated transgenic mice expressing a constitutively active form of Akt (myristoylated Akt, mAkt) in T cells. Naive transgenic T cells were enlarged and had increased rates of glycolysis compared to control T cells. In addition, mAkt transgenic T cells resisted death-by-neglect upon in vitro culture. Upon activation, mAkt-transgenic T cells were less dependent than control cells on costimulation through CD28 and could both grow rapidly and secrete cytokines in the absence of CD28 ligation. In addition, transgenic expression of mAkt led to the accumulation of CD4 T cells and B cells with age. Many aged mAkt-transgenic mice also developed autoimmunity with immunoglobulin deposits on kidney glomeruli and displayed increased incidence of lymphoma. Together, these data show that Akt activation is sufficient to increase basal T cell size and metabolism. Enhancement of T cell metabolism by Akt and more rapid CD28-independent T cell growth may contribute to the accumulation of excess immune cells and the development of lymphoma and autoimmunity.

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The CD28 Signaling Pathway Regulates Glucose Metabolism

Cited by 1,268 publications

References 51 publications

An active mitochondrial biogenesis occurs during dendritic cell differentiation

An active mitochondrial biogenesis occurs during dendritic cell differentiation

T-cell development of resistance to apoptosis is driven by a metabolic shift in carbon source and altered activation of death pathways

Activated Akt promotes increased resting T cell size, CD28‐independent T cell growth, and development of autoimmunity and lymphoma

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