Natural Killer Cells from the Subcutaneous Adipose Tissue Underexpress the NKp30 and NKp44 in Obese Persons and Are Less Active against Major Histocompatibility Complex Class I Non-Expressing Neoplastic Cells

Shoae-Hassani, Alireza; Behfar, Maryam; Mortazavi-Tabatabaei, Seyed Abdolreza; Ai, Jafar; Mohseni, Rashin; Hamidieh, Amir Ali

doi:10.3389/fimmu.2017.01486

Cited by 21 publications

(23 citation statements)

References 47 publications

(49 reference statements)

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“…In accordance to previous studies, no significant differences in NKG2D expression were detected within total NK cells between the BMI groups (53,75,(84)(85)(86)(87). In contrast, other studies demonstrated altered NKG2D expression in obese individuals, although with conflicting results.…”

Section: Aside Of This the Expression Of The Activating Counterpartsupporting

confidence: 89%

Characterization of Surface Receptor Expression and Cytotoxicity of Human NK Cells and NK Cell Subsets in Overweight and Obese Humans

et al. 2020

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Obesity is associated with an increased risk for several cancer types and an altered phenotype and functionality of natural killer (NK) cells. This study aimed to investigate the association of overweight and obesity with NK cell functions and receptor expression profiles in humans. Therefore, peripheral blood mononuclear cells were isolated from normal weight, overweight, and obese healthy blood donors. In depth analysis of immune cell populations and 23 different surface markers, including NK cell receptors, NK-cell-related markers as well as functional intracellular markers on total NK cells and NK subgroups were performed by multicolor flow cytometry. The data revealed a decreased expression of the activating NK cell receptors KIR2DS4 and NKp46 as well as an increased expression of the inhibitory NK cell receptors NKG2A and Siglec-7 in overweight and obese compared to normal weight individuals. Additionally, the expression of the adhesion molecule CD62L and the maturation and differentiation marker CD27 was downregulated in NK cells of overweight and obese subjects. Furthermore, the cytotoxicity of NK cells against colorectal cancer cells was decreased in overweight and obese subjects. Investigations on underlying killing mechanisms demonstrated a reduced TRAIL expression on NK cells of obese subjects suggesting an impaired death receptor pathway in obesity. The present study gives new insights into an impaired functionality and phenotype of NK cells and NK cell subsets in overweight and obesity. These phenotypic alterations and dysfunction of NK cells might be an explanation for the increased cancer risk in obesity.

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Section: Aside Of This the Expression Of The Activating Counterpartsupporting

confidence: 89%

Characterization of Surface Receptor Expression and Cytotoxicity of Human NK Cells and NK Cell Subsets in Overweight and Obese Humans

et al. 2020

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“…In accordance to the results in mice and rats, obesity was shown to be associated with a decreased NK cell number in blood, liver, uterine, or colon tissue in humans (74,99,(146)(147)(148)(149), whereas several other studies did not observe any differences in the NK cell number comparing normal-weight and obese humans (71,72,84,(150)(151)(152)(153)(154)(155) (Table 4). These discrepancies may be caused by the use of different markers and methods to identify NK cells and subsets in blood and different tissues and individual parameters in the study population, like gender, BMI, ethnicity, and nutritional or metabolic variances.…”

Section: Effects Of Systemic Obesity On Human Nk Cellssupporting

confidence: 84%

“…Investigating the expression of activating NK cell receptors, studies on human subcutaneous adipose tissue NK cells demonstrated that the expression of the NKp30 and NKp44 receptors were decreased in obese subjects, whereas the NKG2D expression levels were not affected by obesity (155). These data indicate a reduced cytolytic activity of NK cells in subcutaneous adipose tissue of obese subjects, which might contribute to the higher susceptibility to infections and increased cancer risk under obese conditions.…”

Section: Tissue-resident Nk Cells In Adipose Tissue Of Obese Individualsmentioning

confidence: 94%

“…Analyzing the functionality of adipose tissue-resident NK cells, animal studies demonstrated an increased secretion of IL-6, IFN-γ, and TNF-α by NK cells isolated from visceral and subcutaneous adipose tissue of obese mice (132,134,135). In subcutaneous adipose tissue of obese individuals, a shift from the cytotoxic CD56 dim NK cell subset to the cytokine secreting CD56 bright NK cell subpopulation could be observed (155). This might be one explanation for the increased cytokine secretion of adipose tissue NK cells in obesity.…”

Section: Tissue-resident Nk Cells In Adipose Tissue Of Obese Individualsmentioning

confidence: 99%

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Obesity-Associated Alterations of Natural Killer Cells and Immunosurveillance of Cancer

et al. 2020

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Obesity is accompanied by a systemic chronic low-grade inflammation as well as dysfunctions of several innate and adaptive immune cells. Recent findings emphasize an impaired functionality and phenotype of natural killer (NK) cells under obese conditions. This review provides a detailed overview on research related to overweight and obesity with a particular focus on NK cells. We discuss obesity-associated alterations in subsets, distribution, phenotype, cytotoxicity, cytokine secretion, and signaling cascades of NK cells investigated in vitro as well as in animal and human studies. In addition, we provide recent insights into the effects of physical activity and obesity-associated nutritional factors as well as the reduction of body weight and fat mass on NK cell functions of obese individuals. Finally, we highlight the impact of impaired NK cell physiology on obesity-associated diseases, focusing on the elevated susceptibility for viral infections and increased risk for cancer development and impaired treatment response.NK cells are large granular lymphocytes that mediate rapid innate immunity against viruses, bacteria, parasites, and tumor cells without prior sensitization. NK cells primarily develop and mature in the bone marrow, migrate through the bloodstream, and seed into secondary lymphoid organs, like thymus, spleen, and lymph nodes as well as in other peripheral tissues, like lung, liver, kidney, uterus, and the gastrointestinal tract (23). In blood, NK cells represent 1-6% of all leukocytes and comprise up to 15% of human peripheral blood mononuclear cells (PBMCs). Human NK cells have been defined by the expression of adhesion molecule CD56 and by the absence of the T cell marker CD3. Based on their expression level of CD56 and the Fcγ receptor CD16, NK cells are subdivided into different subpopulations. The two major and classically defined subsets are the CD56 dim CD16 bright NK cells and the CD56 bright CD16 dim/neg NK cells. CD56 dim CD16 bright NK cells represent about 90% of all NK cells and are predominantly found in peripheral blood (24). They are mostly responsible for cytotoxic activity and target cell killing but are also a source of pro-inflammatory Abbreviations: ACM, adipocyte-conditioned media; Adamts3, a disintegrin-like and metallopeptidase with thrombospondin type 1 motif, 3; AdipoR, adiponectin receptor; Anxa8, annexin A8; AT, adipose tissue; Bax, Bcl-2-associated X protein; Bcl, B-cell lymphoma; BMI, body mass index; CCR, CC chemokine receptor; Csf1r, colony stimulating factor 1 receptor; CX3CR1, C-X3-C-motif chemokine receptor 1; DNAM-1, DNAX accessory molecule-1; ESR, estrogen receptor; FasL, Fas ligand; IFN-γ, interferon; GM-CSF; granulocyte macrophage colony-stimulating factor; H6pd, hexose-6-phosphate dehydrogenase; Hk2, hexokinase 2; IL, interleukinIL-6R; interleukin-6 receptor; Il18rap, interleukin 18 receptor accessory protein; IP-10, interferon gamma-induced protein 10; JAK, Janus kinase; KIR, killer immunoglobulin-like receptor; Klra1, killer lectin-like receptor subfamil...

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“…In addition, O'Rourke and colleagues reported an activated phenotype also for AT resident NK cells that, in obesity, upregulate the NKG2D receptor ( 20 ). Although the total NK cell number is similar in blood and AT of lean and obese subjects, affected or not by CRC, NK cells residing in SAT of obese individuals display a poor cytotoxicity against target tumor cells ( 19 , 28 , 30 ). Moreover, reduced NK cell survival and expansion of IL-10-producing NK cells have been described in other obesity-associated cancers ( 43 ).…”

Section: Innate Lymphocyte Profiles In Obesity and Colorectal Cancermentioning

confidence: 99%

Innate Lymphocytes in Adipose Tissue Homeostasis and Their Alterations in Obesity and Colorectal Cancer

2018

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Colorectal cancer (CRC) is the third most common cancer worldwide and a leading cause of death, with burden expected to increase in the coming years. Enhanced adiposity, particularly visceral fat, is associated with increased cancer incidence representing an important indicator of survival, prognosis, recurrence rates, and response to therapy for several tumors including CRC. Compelling evidence has been achieved that the low-grade chronic inflammation characterizing obesity represents a main factor that can favor carcinogenesis. Adipocytes and adipose tissue (AT) infiltrating immune cells contribute to obesity-related inflammation by releasing soluble factors affecting, both locally and systemically, the function of several cell types, including immune and cancer cells. The unbalanced production of immune mediators as well as the profound changes in the repertoire and activation state of immune cells in AT of obese subjects represent key events in the processes that set the basis for a pro-tumorigenic microenvironment. AT harbors a unique profile of immune cells of different origin that play an important role in tissue homeostasis. Among these, tissue-resident innate lymphocytes are emerging as important AT components whose depletion/aberrant activation occurring in obesity could have an impact on inflammation and immune-surveillance against tumors. However, a direct link between obesity-induced dysfunction and cancer development has not been demonstrated yet. In this review, we provide an overview of human obesity- and CRC-induced alterations of blood and adipose tissue-associated innate lymphocytes, and discuss how the adipose tissue microenvironment in obesity might influence the development of CRC.

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Natural Killer Cells from the Subcutaneous Adipose Tissue Underexpress the NKp30 and NKp44 in Obese Persons and Are Less Active against Major Histocompatibility Complex Class I Non-Expressing Neoplastic Cells

Cited by 21 publications

References 47 publications

Characterization of Surface Receptor Expression and Cytotoxicity of Human NK Cells and NK Cell Subsets in Overweight and Obese Humans

Characterization of Surface Receptor Expression and Cytotoxicity of Human NK Cells and NK Cell Subsets in Overweight and Obese Humans

Obesity-Associated Alterations of Natural Killer Cells and Immunosurveillance of Cancer

Innate Lymphocytes in Adipose Tissue Homeostasis and Their Alterations in Obesity and Colorectal Cancer

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