Effects of hypoxia and/or lack of glucose on cellular energy metabolism and cytokine production in stimulated human CD4+ T lymphocytes

Dziurla, René; Gaber, Timo; Fangradt, Monique; Hahne, M.; Tripmacher, Robert; Kolar, Paula; Spies, Cornelia M.; Burmester, G.-R.; Buttgereit, Frank

doi:10.1016/j.imlet.2010.02.008

Cited by 37 publications

(43 citation statements)

References 53 publications

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“…Besides glycolysis, OXPHOS is also immediately elevated upon anti-CD3/CD28 stimulation in T cells and supports the transition from quiescent to effector cells (41, 43, 63). OXPHOS can compensate for glucose restriction and IFNγ production is maintained (41, 64, 65). Moreover, mitochondrial ROS production synergizes with Ca 2+ influx to activate NF-kB and AP-1 (66, 67) and is important for antigen-specific T cell activation (68).…”

Section: Immune Cell Metabolismmentioning

confidence: 99%

Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment

et al. 2017

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Cytotoxic T lymphocytes and NK cells play an important role in eliminating malignant tumor cells and the number and activity of tumor-infiltrating T cells represent a good marker for tumor prognosis. Based on these findings, immunotherapy, e.g., checkpoint blockade, has received considerable attention during the last couple of years. However, for the majority of patients, immune control of their tumors is gray theory as malignant cells use effective mechanisms to outsmart the immune system. Increasing evidence suggests that changes in tumor metabolism not only ensure an effective energy supply and generation of building blocks for tumor growth but also contribute to inhibition of the antitumor response. Immunosuppression in the tumor microenvironment is often based on the mutual metabolic requirements of immune cells and tumor cells. Cytotoxic T and NK cell activation leads to an increased demand for glucose and amino acids, a well-known feature shown by tumor cells. These close metabolic interdependencies result in metabolic competition, limiting the proliferation, and effector functions of tumor-specific immune cells. Moreover, not only nutrient restriction but also tumor-driven shifts in metabolite abundance and accumulation of metabolic waste products (e.g., lactate) lead to local immunosuppression, thereby facilitating tumor progression and metastasis. In this review, we describe the metabolic interplay between immune cells and tumor cells and discuss tumor cell metabolism as a target structure for cancer therapy. Metabolic (re)education of tumor cells is not only an approach to kill tumor cells directly but could overcome metabolic immunosuppression in the tumor microenvironment and thereby facilitate immunotherapy.

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Section: Immune Cell Metabolismmentioning

confidence: 99%

Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment

et al. 2017

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“…A decrease in ATP levels has been logically envisaged, since cells rely more on glycolysis (which is less efficient at producing energy) than on the impaired oxidative phosphorylation under hypoxia. However, this has been refuted since T cells were able to maintain the same intracellular levels of ATP under hypoxia 36,39,41 . Whether HIF-1α stabilization is directly responsible for the decrease in cell expansion is not clear for mature T cells, 19,34,60 although in thymocytes it leads to disrupted TCR signal transduction (via an altered Ca 2+ response) 61 .…”

Section: Hypoxia and Reactivation Of Cd8+ T Cellsmentioning

confidence: 99%

Hypoxia and antitumor CD8⁺ T cells: An incompatible alliance?

2016

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T Lymphocytes face pathologically low O2 tensions within the tumor bed at which they will have to function in order to impact on the malignancy. Recent studies highlighting the importance of O2 and hypoxia-inducible factors for CD8+ T-cell function and fate must now be integrated into tumor immunology concepts if immunotherapies are to progress. Here, we discuss, reinterpret, and reconcile the many apparent contradictions in these data and we propose that O2 is a master regulator of the CD8+ T-cell response. Certain T cell functions are enhanced, others suppressed, but on balance, hypoxia is globally detrimental to the antitumor response.

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“…We and others have demonstrated that immune cells can adapt to such conditions and thus continue to fulfill their effector functions. [18][19][20] Recently, we were also able to show that human cells present in the fracture hematoma do express genes associated with infalammation. 21 Moreover, immunologically restricted patients-who are known to often suffer from impaired fracture healing-exhibit an inadequate response to hypoxia in fracture hematomas with an overshooting inflammatory response.…”

Section: Introductionmentioning

confidence: 95%

Human immune cells' behavior and survival under bioenergetically restricted conditions in an in vitro fracture hematoma model

et al. 2013

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The initial inflammatory phase of bone fracture healing represents a critical step for the outcome of the healing process. However, both the mechanisms initiating this inflammatory phase and the function of immune cells present at the fracture site are poorly understood. In order to study the early events within a fracture hematoma, we established an in vitro fracture hematoma model: we cultured hematomas forming during an osteotomy (artificial bone fracture) of the femur during total hip arthroplasty (THA) in vitro under bioenergetically controlled conditions. This model allowed us to monitor immune cell populations, cell survival and cytokine expression during the early phase following a fracture. Moreover, this model enabled us to change the bioenergetical conditions in order to mimic the in vivo situation, which is assumed to be characterized by hypoxia and restricted amounts of nutrients. Using this model, we found that immune cells adapt to hypoxia via the expression of angiogenic factors, chemoattractants and pro-inflammatory molecules. In addition, combined restriction of oxygen and nutrient supply enhanced the selective survival of lymphocytes in comparison with that of myeloid derived cells (i.e., neutrophils). Of note, non-restricted bioenergetical conditions did not show any similar effects regarding cytokine expression and/or different survival rates of immune cell subsets. In conclusion, we found that the bioenergetical conditions are among the crucial factors inducing the initial inflammatory phase of fracture healing and are thus a critical step for influencing survival and function of immune cells in the early fracture hematoma.

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Effects of hypoxia and/or lack of glucose on cellular energy metabolism and cytokine production in stimulated human CD4+ T lymphocytes

Cited by 37 publications

References 53 publications

Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment

Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment

Hypoxia and antitumor CD8⁺ T cells: An incompatible alliance?

Human immune cells' behavior and survival under bioenergetically restricted conditions in an in vitro fracture hematoma model

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Effects of hypoxia and/or lack of glucose on cellular energy metabolism and cytokine production in stimulated human CD4+ T lymphocytes

Cited by 37 publications

References 53 publications

Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment

Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment

Hypoxia and antitumor CD8+ T cells: An incompatible alliance?

Human immune cells' behavior and survival under bioenergetically restricted conditions in an in vitro fracture hematoma model

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Hypoxia and antitumor CD8⁺ T cells: An incompatible alliance?