Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system

Cho, Sung Hoon; Raybuck, Ariel; Stengel, Kristy R.; Mao, Wei; Beck, Thomas C.; Volanakis, Emmanuel J.; Thomas, James W.; Hiebert, Scott W.; Haase, Volker H.; Boothby, Mark

doi:10.1038/nature19334

Cited by 228 publications

(361 citation statements)

References 36 publications

(54 reference statements)

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“…This was first observed in B-lymphoid tumor cells (Kharas et al, 2008; Wlodarski et al, 2005) and in mouse splenic B cell subsets (Donahue and Fruman, 2007), and later in CD8 + T cells (Salmond et al, 2009). mTORC1 activity in B cells is highly dependent on nutrients in vitro (Donahue and Fruman, 2007; Wlodarski et al, 2005) and suppressed under hypoxic conditions in germinal centers (Cho et al, 2016; Jellusova et al, 2017). Similarly, in activated CD8 + T cells, leucine uptake via the system L amino acid transporter Slc7a5 is required for mTORC1 activity, c-Myc translation and metabolic reprogramming (Sinclair et al, 2013) whereas PI3K/AKT signaling is dispensable for these outcomes (Macintyre et al, 2011).…”

Section: Pi3k In Innate and Adaptive Immunitymentioning

confidence: 99%

The PI3K Pathway in Human Disease

Fruman

Chiu

Hopkins

et al. 2017

Cell

1,757

1,506

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Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers, and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases.

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Section: Pi3k In Innate and Adaptive Immunitymentioning

confidence: 99%

The PI3K Pathway in Human Disease

Fruman

Chiu

Hopkins

et al. 2017

Cell

1,757

1,506

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“…Similarly, in T cells, HIF is important for the regulation of not only survival and differentiation but also proliferation and antitumour capacity 33 . In B cells, HIF also regulates survival, in addition to development and antibody processing 52 . Finally, in intestinal epithelial cells (a key innate immune cell), HIF modulates ion transport, antimicrobial peptide production and barrier function 44,53,54 .…”

Section: Hif Modulation Of Immune Cell Functionmentioning

confidence: 99%

“…For example, a controlled oxygen gradient is sustained in the intestinal mucosa by the juxtaposition of the rich capillary network of the mucosal vasculature (which supplies the mucosa with oxygen) with the anoxic lumen of the gut. Furthermore, in the light zones of germinal centres (GCs), the consumption of oxygen during lymphocyte–DC matching dictates the controlled oxygen gradient, which in turn controls B cell function 52 . Despite this, fluctuations in physiological oxygen gradients can occur.…”

Section: Niche Features That Shape the Hif Responsementioning

confidence: 99%

“…For example, the levels of mucosal oxygen increase substantially following the consumption of a meal, when mucosal blood flow is considerably increased. In addition, GC oxygen levels drop during the clonal expansion of B cells, which occurs following the presentation of a receptor-specific antigen 52 . These changes can be considered physiological fluctuations in tissue oxygen levels.…”

Section: Niche Features That Shape the Hif Responsementioning

confidence: 99%

“…Fifth, the limited vasculature of the retina renders it hypoxic in the normal physiological state 142 . Sixth, physiological hypoxia in the light zone of the germinal centres of lymph nodes occurs as a result of the high level of oxygen consumption associated with dendritic cell–B cell matching 52 .…”

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confidence: 99%

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Regulation of immunity and inflammation by hypoxia in immunological niches

2017

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Immunological niches are focal sites of immune activity that can have varying microenvironmental features. Hypoxia is a feature of physiological and pathological immunological niches. The impact of hypoxia on immunity and inflammation can vary depending on the microenvironment and immune processes occurring in a given niche. In physiological immunological niches, such as the bone marrow, lymphoid tissue, placenta and intestinal mucosa, physiological hypoxia controls innate and adaptive immunity by modulating immune cell proliferation, development and effector function, largely via transcriptional changes driven by hypoxia-inducible factor (HIF). By contrast, in pathological immunological niches, such as tumours and chronically inflamed, infected or ischaemic tissues, pathological hypoxia can drive tissue dysfunction and disease development through immune cell dysregulation. Here, we differentiate between the effects of physiological and pathological hypoxia on immune cells and the consequences for immunity and inflammation in different immunological niches. Furthermore, we discuss the possibility of targeting hypoxia-sensitive pathways in immune cells for the treatment of inflammatory disease.

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Lipid metabolism in B cell biology

Peeters,

Jellusova

2023

Molecular Oncology

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In recent years, the field of immunometabolism has solidified its position as a prominent area of investigation within the realm of immunological research. An expanding body of scientific literature has unveiled the intricate interplay between energy homeostasis, signalling molecules, and metabolites in relation to fundamental aspects of our immune cells. It is now widely accepted that disruptions in metabolic equilibrium can give rise to a myriad of pathological conditions, ranging from autoimmune disorders to cancer. Emerging evidence, although sometimes fragmented and anecdotal, has highlighted the indispensable role of lipids in modulating the behaviour of immune cells, including B cells. In light of these findings, this review aims to provide a comprehensive overview of the current state of knowledge regarding lipid metabolism in the context of B cell biology.

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Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system

Cited by 228 publications

References 36 publications

The PI3K Pathway in Human Disease

The PI3K Pathway in Human Disease

Regulation of immunity and inflammation by hypoxia in immunological niches

Lipid metabolism in B cell biology

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