Effects of hypoxia on interleukin-2 mRNA expression by T lymphocytes

Zuckerberg, Aaron L.; Goldberg, Lisa I.; Lederman, Howard M.

doi:10.1097/00003246-199402000-00008

Cited by 51 publications

(28 citation statements)

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“…However, simultaneous inhibition of both OXPHOS and glycolysis resulted in a distinct inhibition of cytokine synthesis and, correspondingly, ATP levels were lowest under these conditions. These results are close to earlier observations in murine cytotoxic T cells [22] and in murine T cell lymphoma cells in which the regulation of IL-2 transcription is sensitive to changes in oxygen tension towards hypoxia [23]. A delayed development of cytotoxic T lymphocytes and an inhibition of the accumulation of IL-2 and IFN-c have been also observed under hypoxia [24].…”

Section: Discussionsupporting

confidence: 90%

Human CD4⁺ T cells maintain specific functions even under conditions of extremely restricted ATP production

Tripmacher¹,

Gaber²,

Dziurla³

et al. 2008

Eur J Immunol

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We investigated the energy-adaptive potential of human CD4(+) T cells under conditions of impaired oxidative phosphorylation (OXPHOS) and/or low glucose (inhibiting glycolysis). These cells often encounter these conditions when executing their functions in injured/inflamed tissues, even though T cells themselves require constant and adequate energy supply via ATP. We assessed two specific functions, cytokine synthesis and proliferation, and addressed whether adaptive characteristics also emerged in vivo. In glucose-containing medium, both cytokine production and proliferation were unaffected, even under complete OXPHOS suppression. Only when glucose was also absent were these functions significantly decreased. Partial recovery of OXPHOS and induced glycolysis were crucial for the maintenance of cellular energy supply. Adaptive regulatory mechanisms are clinically relevant because hypoxia up-regulates glycolytic genes but down-regulates OXPHOS genes in vivo. Our data demonstrate an unexpectedly high, clinically relevant adaptive potential of human CD4(+) T cells to maintain specific functions even under severely impaired bioenergetic conditions.

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Section: Discussionsupporting

confidence: 90%

Human CD4⁺ T cells maintain specific functions even under conditions of extremely restricted ATP production

Tripmacher¹,

Gaber²,

Dziurla³

et al. 2008

Eur J Immunol

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“…Hypoxia was shown to decrease T-cell survival (29), and incubation of na€ ve T cells under hypoxia decreases their secretion of the trophic cytokine IL2 in a HIF1-dependent manner (30). CD4 þ and CD8 þ T cells derived from HIF1a-deficient mice exhibit increased proliferation, produce higher levels of interferon-g, and display increased antitumor responses (31).…”

Section: Direct Effects Of Hypoxia On Immune Effectorsmentioning

confidence: 99%

Mechanisms of Hypoxia-Mediated Immune Escape in Cancer

et al. 2014

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An important aspect of malignant progression is the acquired ability of tumor cells to avoid recognition and destruction by the immune system (immune escape). Clinical cancer progression is also associated with the development of tumor hypoxia, which is mechanistically linked to the acquisition of malignant phenotypes in cancer cells. Despite the well-established role of hypoxia in tumor cell invasion and metastasis, and resistance to therapy, relatively few studies have examined the contribution of hypoxia to cancer immune escape. Accumulating evidence reveals that hypoxia can impair anticancer immunity by altering the function of innate and adaptive immune cells and/or by increasing the intrinsic resistance of tumor cells to the cytolytic activity of immune effectors. Here, we discuss certain aspects of the contribution of hypoxia to tumor immune escape and provide evidence for a novel role of cyclic guanosine monophosphate (cGMP) signaling in the regulation of hypoxia-induced immune escape. Thus, we propose that activation of cGMP signaling in cancer cells may have important immunotherapeutic applications. Cancer Res; 74(24); 7185-90. Ó2014 AACR.

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“…This is expected if the decrease in proliferation during hypoxia is mediated by the hypoxic inhibition of the Kv1.3 channels. Thus, we have measured the levels of Kv1.3 ␣ subunits in the N; lanes 1-4), in hypoxia (H; 1% O 2 , ϳ8 mmHg, lanes [5][6][7][8] and in normoxia in presence of 8.6 mM 4-AP (lanes 9 -11) for 24 h. A total of 40 g total lysate was loaded in each lane. B, Averaged Kv␤2 protein levels Jurkat cells cultured in normoxia (N; n ϭ 10), hypoxia (H; n ϭ 11), and normoxia in presence of 4-AP (n ϭ 3) for 24 h. Data were normalized to the amount of ␤-actin and expressed as percentage of control (normoxia).…”

Section: Hypoxia Selectively Inhibits Proliferation Generated By Tcr mentioning

confidence: 99%

“…Thus, hypoxia might affect normal immune cell development as well as immune cell activity at hypoxic pathological sites. Indeed, various in vitro studies have indicated that hypoxia can affect the function of the host immune cells (5)(6)(7)(8)(9). Hypoxia has been shown to markedly diminish lymphocyte expression of IL-2, proliferation, and to impair the activity of NK cells (7,8,10).…”

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confidence: 99%

Hypoxia Regulates Expression and Activity of Kv1.3 Channels in T Lymphocytes: A Possible Role in T Cell Proliferation

Conforti

Petrović²,

Mohammad³

et al. 2003

The Journal of Immunology

103

108

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T lymphocytes are exposed to hypoxia during their development and also when they migrate to hypoxic pathological sites such as tumors and wounds. Although hypoxia can affect T cell development and function, the mechanisms by which immune cells sense and respond to changes in O2-availability are poorly understood. K+ channels encoded by the Kv1.3 subtype of the voltage-dependent Kv1 gene family are highly expressed in lymphocytes and are involved in the control of membrane potential and cell function. In this study, we investigate the sensitivity of Kv1.3 channels to hypoxia in freshly isolated human T lymphocytes and leukemic Jurkat T cells. Acute exposure to hypoxia (20 mmHg, 2 min) inhibits Kv1.3 currents in both cell types by 20%. Prolonged exposure to hypoxia (1% O2 for 24 h) selectively decreases Kv1.3 protein levels in Jurkat T cells by 47%, but not Kvβ2 and SK2 Ca-activated K+ channel subunit levels. The decrease in Kv1.3 protein levels occurs with no change in Kv1.3 mRNA expression and is associated with a significant decrease in K+ current density. A decrease in Kv1.3 polypeptide levels similar to that obtained during hypoxia is produced by Kv1.3 channel blockage. Our results indicate that hypoxia produces acute and long-term inhibition of Kv1.3 channels in T lymphocytes. This effect could account for the inhibition of lymphocyte proliferation during hypoxia. Indeed, we herein present evidence showing that hypoxia selectively inhibits TCR-mediated proliferation and that this inhibition is associated with a decrease in Kv1.3 proteins.

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Effects of hypoxia on interleukin-2 mRNA expression by T lymphocytes

Cited by 51 publications

References 0 publications

Human CD4⁺ T cells maintain specific functions even under conditions of extremely restricted ATP production

Human CD4⁺ T cells maintain specific functions even under conditions of extremely restricted ATP production

Mechanisms of Hypoxia-Mediated Immune Escape in Cancer

Hypoxia Regulates Expression and Activity of Kv1.3 Channels in T Lymphocytes: A Possible Role in T Cell Proliferation

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Effects of hypoxia on interleukin-2 mRNA expression by T lymphocytes

Cited by 51 publications

References 0 publications

Human CD4+ T cells maintain specific functions even under conditions of extremely restricted ATP production

Human CD4+ T cells maintain specific functions even under conditions of extremely restricted ATP production

Mechanisms of Hypoxia-Mediated Immune Escape in Cancer

Hypoxia Regulates Expression and Activity of Kv1.3 Channels in T Lymphocytes: A Possible Role in T Cell Proliferation

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Human CD4⁺ T cells maintain specific functions even under conditions of extremely restricted ATP production

Human CD4⁺ T cells maintain specific functions even under conditions of extremely restricted ATP production