Genetic deletion of the <scp>HIF</scp>‐1α isoform I.1 in <scp>T</scp> cells enhances antibacterial immunity and improves survival in a murine peritonitis model

Georgiev, Peter; Belikoff, Bryan; Hatfield, Stephen; Ohta, Akio; Sitkovsky, Michail V.; Lukashev, Dmitriy

doi:10.1002/eji.201242765

Cited by 19 publications

(15 citation statements)

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“…These observations indicated that hypoxia inhibited Th1-type cell activation and were consistent with an earlier report of increased inflammation and autoimmunity in chimeric mice with HIF-1α deletion in cells of the adaptive immune system [52]. Another study highlights the immunosuppressive role of the activation-inducible isoform HIF-1α isoform I.1 in T cells during bacterial sepsis [53]. In addition, recent evidence suggests that hypoxia may differentially regulate the balance of Th17/Treg cells in vivo [54].…”

Section: T Lymphocytessupporting

confidence: 88%

Hypoxia in the intestine or solid tumors: A beneficial or deleterious alarm signal?

2014

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IntroductionThe availability of oxygen in the atmosphere provided protozoans with the ability to meet higher energy demands required for the development of complex multicellular organisms. Consequently, oxygen-dependent cells developed mechanisms to sense and adapt to changes in oxygen levels [1]. In mammals the respiratory, circulatory and nervous system work together to ensure that oxygen levels are precisely maintained, because excess or deficiency of oxygen can lead to cell death and tissue damage [2].The level of oxygen in mammalian tissues is much lower than that in the atmosphere (oxygen partial tension (PO 2 ) = 21.2 kPa). Tissue oxygen can range between 13 kPa in the pulmonary vein down to 2.7 kPa at the interstitial spaces. Intracellular oxygen ranges from 1.3 to 2.7 kPa [3]. In this context, hypoxia is defined as a deficiency in tissue or blood oxygen as compared to physiological levels. HIF-1α has been shown to be stabilized at a PO 2 lower than 2kPa [4].One molecule that plays an important role in mediating adaptive functions to oxygen levels is the hypoxia inducible transcription factor (HIF)-1. HIF-1 is a transcription factor composed of Correspondence: Prof. Muriel Moser e-mail: mmoser@ulb.ac.be two subunits, HIF-1α and HIF-1β (or aryl hydrocarbon receptor nuclear translocator). The beta subunit of HIF is constitutively expressed in mammalian cells, whereas, in the presence of oxygen, the alpha subunit is hydroxylated by proline hydroxylases (PHDs), ubiquitinylated by the von Hippel-Lindau (VHL) protein (E3 ubiquitin ligase), and degraded by the proteasome pathway. Hypoxia leads to stabilization of HIF-1α (through the inhibition of oxygen-dependent PHDs), inducing the transcription of multiple genes unique for each cell type, among them erythropoietin, vascular endothelial growth factor, glycolytic enzymes, etc. (for review see [2]). The transcription function of HIF-1 is also negatively regulated in the presence of oxygen by the dioxygenase factor inhibiting HIF that hydroxylates HIF-1α, thereby preventing the recruitment of the transcriptional machinery [5]. Besides the ubiquitously expressed HIF-1, two paralogs exist in mammals that are also regulated by oxygen: HIF-2 is also widely expressed and plays important roles in erythropoiesis, vascularization, pulmonary development and, more specifically, in iron absorption [6,7]; HIF-3 has been shown to negatively regulates HIF-1 and HIF-2 by competing for the binding on HREs of target genes [8]. A recent report, however, clearly demonstrates that zebrafish Hif-3α has strong transactivation activity and that human HIF-3α isoforms upregulate similar target genes in human cells [9]. Finally, it should be noted that, in addition to hypoxia, other mechanisms [12,13]. Although HIFs appear as major sensors of hypoxia, other transcriptional cascades are triggered at low oxygen tension. In particular, the NF-κB pathway was shown to induce Hif-1α and to be activated by hypoxia through p65 and p50 stabilization and nuclear translocation, linking both pathway...

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Section: T Lymphocytessupporting

confidence: 88%

Hypoxia in the intestine or solid tumors: A beneficial or deleterious alarm signal?

2014

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“…These included hif1a exon I.1 (albeit weakly expressed, as judged by Nanostring absolute RNA counts (data not shown)), hif2a , vegfa , glut1 , entpd1 (CD39), galectin3 , gelsolin , and tnfrsf9 (CD137). However, hif1a , adora2a (A2AR), and hif1b were not modulated, hif3a was not expressed, while nt5e (CD73) was downregulated (Fig. A).…”

Section: Resultsmentioning

confidence: 97%

Phenotypic switch of CD8⁺ T cells reactivated under hypoxia toward IL‐10 secreting, poorly proliferative effector cells

et al. 2015

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CD8+ T cells controlling pathogens or tumors must function at sites where oxygen tension is frequently low, and never as high as under atmospheric culture conditions. However, T-cell function in vivo is generally analyzed indirectly, or is extrapolated from in vitro studies under nonphysiologic oxygen tensions. In this study, we delineate the role of physiologic and pathologic oxygen tension in vitro during reactivation and differentiation of tumor-specific CD8 + T cells. Using CD8 + T cells from pmel-1 mice, we observed that the generation of CTLs under 5% O 2 , which corresponds to physioxia in lymph nodes, gave rise to a higher effector signature than those generated under atmospheric oxygen fractions (21% O 2 ). Hypoxia (1% O 2 ) did not modify cytotoxicity, but decreasing O 2 tensions during CTL and CD8 + tumor-infiltrating lymphocyte reactivation dose-dependently decreased proliferation, induced secretion of the immunosuppressive cytokine IL-10, and upregulated the expression of CD137 (4-1BB) and CD25. Overall, our data indicate that oxygen tension is a key regulator of CD8 + T-cell function and fate and suggest that IL-10 release may be an unanticipated component of CD8 + T cell-mediated immune responses in most in vivo microenvironments. Keywords: CD8+ T cell r Oxygen r Hypoxia r IL-10 r T-cell reactivation Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIn a healthy physiologic context, oxygen tensions in mammalian tissues are tightly regulated, but still show significant variation both between tissues and within the same tissue (Supporting Information Fig. 1A) [1][2][3]. However, oxygen tensions are far below physiologic values in different pathologic conditions, mostly involving inflammation [4], solid tumors [5,6], and infections [7]. In contrast to sufficient oxygen supply (i.e. normoxia), oxygen deprivation (i.e. hypoxia) leads to cellular responses involving Correspondence: Dr. Paul R. Walker e-mail: Paul.Walker@hcuge.ch stabilization of HIFs (hypoxia-inducible factors), transcription factors that are composed of an inducible α-subunit (i.e. HIF-1α, HIF-2α, or HIF-3α) together with a constitutive β-subunit (i.e. HIF-1β, HIF-2β, or HIF-3β) [8]. Upon stabilization, HIFs transcribe various genes with HIF-responsive elements in their promoter; these include those that increase angiogenesis (e.g. VEGF) and glucose metabolism (e.g. glucose transporters) [9]. Interestingly, HIF-1α and HIF-2α can have unique, redundant, or opposing roles [9,10]. Furthermore, while HIF-1α is described to be stabilized and active below 2% O 2 in an acute manner, HIF-2α has been shown to be stable below 5% O 2 in a chronic manner [11,12]. However, although HIFs are central to many hypoxia responses, certain effects have been shown to be HIF-independent [13][14][15]. Intriguingly, HIF-1α can also be involved in immune cell activation Eur. J. Immunol. 2015Immunol. . 45: 2263Immunol. -2275 under atmospheric oxygen fractions (AtO 2 ; i.e. 21%), as rep...

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“…As IL-17 has been shown to inhibit IFNγ production, it has been proposed that the increase in IFNγ in these mice is due to decreased IL-17 production 55 . Nonetheless, follow-up studies have revealed that deletion of the HIF1α isoform I.1 in T cells enhances immunity in a model of bacterial infection 61 . Therefore, the precise role of HIF1α in T H 1 and T H 2 cell differentiation and function remains to be determined.…”

Section: Metabolic Regulation Of Cd4+ Th Cell Lineagesmentioning

confidence: 99%

Integrating canonical and metabolic signalling programmes in the regulation of T cell responses

2014

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Over the past decade, our understanding of T cell activation, differentiation and function has markedly expanded, providing a greater appreciation of the signals and pathways that regulate these processes. It has become clear that evolutionarily conserved pathways that regulate stress responses, metabolism, autophagy and survival have crucial and specific roles in regulating T cell responses. Recent studies suggest that the metabolic pathways involving MYC, hypoxia-inducible factor 1α (HIF1α), AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are activated upon antigen recognition and that they are required for directing the consequences of T cell receptor engagement. The purpose of this Review is to provide an integrated view of the role of these metabolic pathways and of canonical T cell signalling pathways in regulating the outcome of T cell responses.

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Genetic deletion of the HIF‐1α isoform I.1 in T cells enhances antibacterial immunity and improves survival in a murine peritonitis model

Cited by 19 publications

References 54 publications

Hypoxia in the intestine or solid tumors: A beneficial or deleterious alarm signal?

Hypoxia in the intestine or solid tumors: A beneficial or deleterious alarm signal?

Phenotypic switch of CD8⁺ T cells reactivated under hypoxia toward IL‐10 secreting, poorly proliferative effector cells

Integrating canonical and metabolic signalling programmes in the regulation of T cell responses

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Genetic deletion of the HIF‐1α isoform I.1 in T cells enhances antibacterial immunity and improves survival in a murine peritonitis model

Cited by 19 publications

References 54 publications

Hypoxia in the intestine or solid tumors: A beneficial or deleterious alarm signal?

Hypoxia in the intestine or solid tumors: A beneficial or deleterious alarm signal?

Phenotypic switch of CD8+ T cells reactivated under hypoxia toward IL‐10 secreting, poorly proliferative effector cells

Integrating canonical and metabolic signalling programmes in the regulation of T cell responses

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Phenotypic switch of CD8⁺ T cells reactivated under hypoxia toward IL‐10 secreting, poorly proliferative effector cells