Invariant NKT cells and CD1d<sup>+</sup> cells amass in human omentum and are depleted in patients with cancer and obesity

Lynch, Lydia; O’Shea, Donal; Winter, Desmond C.; Geoghegan, Justin; Doherty, Derek G.; O’Farrelly, Cliona

doi:10.1002/eji.200939349

Cited by 229 publications

(226 citation statements)

References 44 publications

(105 reference statements)

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“…examination of human peritoneal samples confirmed such findings (89). Analysis revealed up to 15% of NKt cells in the peritoneum depending on the nKt cell subtypes (10% inKt, 15% with cD1d expression) compared to ~1% in peripheral blood.…”

Section: Dm Obesity and The Immune Systemsupporting

confidence: 60%

“…Analysis revealed up to 15% of NKt cells in the peritoneum depending on the nKt cell subtypes (10% inKt, 15% with cD1d expression) compared to ~1% in peripheral blood. compared to healthy controls with normal BMi, the peritoneal iNKt cell number was significantly lower in morbidly obese subjects (p=0.005) and in subjects with colorectal cancer (p=0.004) (89).…”

Section: Dm Obesity and The Immune Systemmentioning

confidence: 80%

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Molecular basis of carcinogenesis in diabetic patients (Review)

Matyszewski

Czarnecka

Solarek

et al. 2015

International Journal of Oncology

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Abstract. the most important molecular mechanisms promoting carcinogenesis in patients with diabetes mellitus (DM) include oxidative stress, excessive generation of free radicals and nitrous oxide, damage to cellular membranes and Dna, overproduction of lactate, overabundance of protein glycosylation storage products, overexpression of pathological enzyme isoforms, and leakage of cytochromes from organelles. additionally, dysfunctional signal transduction pathways, especially in pathways involving phosphoinositide 3-kinase (Pi3K)/phosphatase and tensin homolog (Pten)/akt, raS/raf/erK, and mammalian target of rapamycin (mtor), have been implicated in malignant transformation and progression. obesity and metabolic disorders, such as DM, may contribute to a dysfunctional immune system with a suppressed immune response by inducing a chronic inflammatory state, abnormal humoral and cellular mediated immunity, and lower counts and activity levels of natural killer (nK) cells and natural killer t cells (nKt cells). recent advances in molecular biology will allow for better understanding of abnormal cellular pathways, as well as elucidating how metabolic disorders contribute to oncogenesis. Knowledge gained through these studies may lead to more efficacious oncologic therapies. Contents1. insulin resistance and hyperinsulinemia 2. abnormal glucose metabolism and colorectal cancer 3. abnormal glucose metabolism and pancreatic cancer 4. abnormal glucose metabolism and liver cancer 5. abnormal glucose metabolism and breast cancer 6. abnormal glucose metabolism and endometrial cancer 7. abnormal glucose metabolism and prostate cancer 8. abnormal glucose metabolism and lung cancer 9. DM, obesity, and the immune system 10. conclusions Insulin resistance and hyperinsulinemiainsulin is a peptide hormone produced by pancreatic β islet cells, it stimulates the transport of glucose, amino acids, and potassium from circulating blood serum into cells. Binding of the insulin molecule to the insulin receptor (ir) on muscle and liver cells stimulates the induction of glycogen synthesis, fatty acid esterification, lipolysis inhibition, protein catabolism, and gluconeogenesis. irs are present in two isoforms, ir a and B. as a result of glucose and amino acid transport

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Section: Dm Obesity and The Immune Systemsupporting

confidence: 60%

Section: Dm Obesity and The Immune Systemmentioning

confidence: 80%

Molecular basis of carcinogenesis in diabetic patients (Review)

Matyszewski

Czarnecka

Solarek

et al. 2015

International Journal of Oncology

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“…This could be a reflection of our in vitro observations, indicating that the direct modulation of CD4 + T cells by adipocytes is a relevant process in the adipose tissue in vivo. Alternatively, it could also be due to differences in composition of the CD4 + T-cell population between peripheral blood and adipose tissue, for example, due to an enrichment in iNKT cells, potent producers of IFN-γ and previously shown to be increased in omental adipose tissue [14]. Although the presence of CD3 + CD4 + Vα24-Jα18 + cells (iNKT cells) was below 1.5% in the IFP of OA patients (n = 5, data not shown), we cannot formally exclude the possibility that these cells were enriched in the IFP of other patients.…”

Section: Discussionmentioning

confidence: 99%

Adipocyte‐derived lipids modulate CD4⁺ T‐cell function

et al. 2013

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Adipose tissue contains several immune cells whose number and phenotype vary depending on the adiposity. In the present study, we show that IFN-γ + CD4 + T cells are enriched in human adipose tissue compared with in blood. To gain insight into the underlying mechanisms, we investigated the possibility that human adipocytes modulate CD4 + T-cell cytokine production and proliferation and show that CD4 + T cells produced increased levels of IFN-γ when activated in the presence of adipocytes. This effect was mediated by soluble mediators, as shown in transwell and adipocyte-conditioned medium (ACM) transfer experiments. Additionally, ACM induced increased proliferation of CD4 + T cells upon activation. Intriguingly, the proliferation-enhancing effect resided mainly in the lipid fraction of ACM, as shown upon separation of the protein and lipid fraction. Further separation of these lipids based on polarity revealed that the modulatory effect is confined to fractions containing free fatty acids. All identified fatty acids were able to individually enhance T-cell proliferation. These data indicate that adipocytes can modulate CD4 + T-cell function through the release of lipids. Remarkably, free fatty acids were the most prominent modulators of T-cell proliferation, possibly leading to an accumulation of these cells in adipose tissue. Keywords: Adipocytes r CD4 + T cells r Lipids r ObesityAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAdipose tissue is composed of adipocytes, which are primarily involved in lipid storage and release, and the stromal vascular fraction (SVF). The composition of the SVF varies, depending on the localization of the adipose tissue and the degree of adiposity of the individual, but it typically contains a large variety Correspondence: Dr. Andreea Ioan-Facsinay e-mail: A.Ioan@lumc.nl of cells, including progenitor cells, fibroblasts, endothelial cells, nerve cells, and immune cells. Among the immune cells described in adipose tissue, macrophages and T cells are the most abundant, but other cells, like NK cells, mast cells, and B cells have also been described (reviewed in [1]). While the precise role of these cells in the adipose tissue is largely unknown, there is increasing evidence that cross-talk between immune cells and adipocytes exists and that the immune cells can influence the metabolic functions of the resident adipocytes (reviewed in [1] [2,3], or local differentiation/proliferation of resident T cells [5] under the influence of the adipose tissue environment could constitute underlying mechanisms for changes in the adipose tissue CD4 + T-cell population in obesity.Adipose tissue T cells have been previously shown to be present in the vicinity of adipocytes [3]. Moreover, some adipocytederived soluble mediators, such as leptin [10, have been shown to modulate differentiation or cytokine production by CD4 + T cells. However, adipocytes can release a large number of soluble mediators with different biologica...

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“…high IL-4 production) as compared with spleen iNKT cells (19). AT-resident iNKT cells are depleted with increased adiposity (15)(16)(17)(18)(19). Recent studies showed the ability of iNKT cells to exert pathogenic and protective effects on AT function and metabolism (15-19, 24 -28).…”

mentioning

confidence: 99%

CD1d-mediated Presentation of Endogenous Lipid Antigens by Adipocytes Requires Microsomal Triglyceride Transfer Protein

Rakhshandehroo

Gijzel

Siersbæk

et al. 2014

Journal of Biological Chemistry

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Background: Natural killer T (NKT) cells in adipose tissue (AT) contribute to whole body energy homeostasis. Results: Lipid antigen presentation genes, including microsomal triglyceride transfer protein (MTP), are switched on during adipocyte differentiation, and affect iNKT cell activity. Conclusion: Adipocytes can communicate with iNKT cells by presenting endogenous and exogenous lipid antigens. Significance: Unraveling adipocyte-iNKT cell communication may help to fight obesity-induced AT dysfunction.

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Invariant NKT cells and CD1d⁺ cells amass in human omentum and are depleted in patients with cancer and obesity

Cited by 229 publications

References 44 publications

Molecular basis of carcinogenesis in diabetic patients (Review)

Molecular basis of carcinogenesis in diabetic patients (Review)

Adipocyte‐derived lipids modulate CD4⁺ T‐cell function

CD1d-mediated Presentation of Endogenous Lipid Antigens by Adipocytes Requires Microsomal Triglyceride Transfer Protein

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Invariant NKT cells and CD1d+ cells amass in human omentum and are depleted in patients with cancer and obesity

Cited by 229 publications

References 44 publications

Molecular basis of carcinogenesis in diabetic patients (Review)

Molecular basis of carcinogenesis in diabetic patients (Review)

Adipocyte‐derived lipids modulate CD4+ T‐cell function

CD1d-mediated Presentation of Endogenous Lipid Antigens by Adipocytes Requires Microsomal Triglyceride Transfer Protein

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Invariant NKT cells and CD1d⁺ cells amass in human omentum and are depleted in patients with cancer and obesity

Adipocyte‐derived lipids modulate CD4⁺ T‐cell function