Morbidly Obese Human Subjects Have Increased Peripheral Blood CD4+ T Cells With Skewing Toward a Treg- and Th2-Dominated Phenotype

Weerd, Kim van der; Dik, Willem A.; Schrijver, Benjamin; Schweitzer, Dave H.; Langerak, Anton W.; Drexhage, Hemmo A.; Kiewiet, Rosalie M.; Aken, Maarten O. van; Huisstede, Astrid van; Dongen, Jacques J. M. van; Lelij, Aart-Jan van der; Staal, Frank J. T.; Hagen, P. Martin van

doi:10.2337/db11-1065

Cited by 153 publications

(133 citation statements)

References 52 publications

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“…Although existing data support the hypothesis that CD8 + cells are the predominant T cell subset in the visceral WAT of obese humans and mice [31,33,45], CD4 + T cells may also regulate insulin sensitivity and adiposity [32]. In line with this, an increased number of activated CD4 + cells has been identified in morbidly obese humans [78]. Second, the mode of action of activated T cells, independent of their CD4 + or CD8 + identity, seems to be through the induction of proinflammatory cytokines, such as TNF-α, IFN-γ, and chemokines, such as CCL2.…”

Section: Conclusion and Future Outlooksupporting

confidence: 51%

Lymphocytes in obesity-related adipose tissue inflammation

et al. 2012

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Inflammation in the white adipose tissue (WAT) is considered a major player in the development of insulin resistance. The role of macrophages accumulating in the WAT during obesity, promoting WAT inflammation and insulin resistance is well established. In contrast, less is known about the role of lymphocytes. Recent studies have implicated different lymphocyte subsets in WAT inflammation. For instance, cytotoxic CD8 + T cells infiltrating the WAT may contribute to the recruitment, differentiation and activation of macrophages. On the other hand, a differential role for CD4 + Th1 and CD4 + Th2 cells has been suggested.Levels of WAT regulatory T cells decrease during the course of obesity and may represent a crucial factor for the maintenance of insulin sensitivity. Moreover, activation of natural killer T cells, an innate-like T cell population, which recognises lipid antigens, promotes insulin resistance and WAT inflammation. Finally, B cells may infiltrate WAT very early in response to high-fat feeding and worsen glucose metabolism through modulation of T cells and the production of pathogenic antibodies. These interesting new findings however bear controversies and introduce novel, yet unanswered, questions. Here, we review and discuss the impact of the different lymphocyte subsets in obesityrelated WAT inflammation and attempt to identify the open questions to be answered by future studies.

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Section: Conclusion and Future Outlooksupporting

confidence: 51%

Lymphocytes in obesity-related adipose tissue inflammation

et al. 2012

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“…Although the T-reg population correlated positively with TNF-α and glycerol secretion, we could not confirm this finding by quantification of FOXP3 expression in the CD4 + T cell fraction (data not shown). In a previous human study, T-reg cells were found to be increased in the peripheral blood of morbidly obese patients, although no correlation with insulin resistance was observed [39]. Clearly the role of this important cell population in type 2 diabetes needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

Increased fat cell size: a major phenotype of subcutaneous white adipose tissue in non-obese individuals with type 2 diabetes

et al. 2015

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Aims/hypothesis We aimed to elucidate the impact of fat cell size and inflammatory status of adipose tissue on the development of type 2 diabetes in non-obese individuals. Methods We characterised subcutaneous abdominal adipose tissue by examining stromal cell populations by 13 colour flow cytometry, measuring expression of adipogenesis genes in the progenitor cell fraction and determining lipolysis and adipose secretion of inflammatory proteins in 14 non-obese men with type 2 diabetes and 13 healthy controls matched for age, sex, body weight and total fat mass. Results Individuals with diabetes had larger fat cells than the healthy controls but stromal cell population frequencies, adipose lipolysis and secretion of inflammatory proteins did not differ between the two groups. However, in the entire cohort fat cell size correlated positively with the ratio of M1/M2 macrophages, TNF-α secretion, lipolysis and insulin resistance. Expression of genes encoding regulators of adipogenesis and adipose morphology (BMP4, CEBPα [also known as CEBPA], PPARγ [also known as PPARG] and EBF1) correlated negatively with fat cell size. Conclusions/interpretation We show that a major phenotype of white adipose tissue in non-obese individuals with type 2 diabetes is adipocyte hypertrophy, which may be mediated by an impaired adipogenic capacity in progenitor cells. Consequently, this could have an impact on adipose tissue inflammation, release of fatty acids, ectopic fat deposition and insulin sensitivity.

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“…15,16 The impact of obesity on the cells of the adaptive immune system has also been reported. 17 DCs are the bridge between innate and adaptive immune responses. They are responsible for activation and polarisation of T cells, providing multiple signals that shape the adaptive immune response.…”

Section: Discussionmentioning

confidence: 99%

Changes in human dendritic cell number and function in severe obesity may contribute to increased susceptibility to viral infection

et al. 2013

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Dendritic cells (DCs) are key immune sentinels linking the innate and adaptive immune systems. DCs recognise danger signals and initiate T-cell tolerance, memory and polarisation. They are critical cells in responding to a viral illness. Obese individuals have been shown to have an impaired response to vaccinations against virally mediated conditions and to have an increased susceptibility to multi-organ failure in response to viral illness. We investigated if DCs are altered in an obese cohort (mean body mass index 51.7 ± 7.3 kg m À 2 ), ultimately resulting in differential T-cell responses. Circulating DCs were found to be significantly decreased in the obese compared with the lean cohort (0.82% vs 2.53%). Following Toll-like receptor stimulation, compared with lean controls, DCs generated from the obese cohort upregulated significantly less CD83 (40% vs 17% mean fluorescence intensity), a molecule implicated in the elicitation of T-cell responses, particularly viral responses. Obese DCs produced twofold more of the immunosuppressive cytokine interleukin (IL)-10 than lean controls, and in turn stimulated fourfold more IL-4-production from allogenic naive T cells. We conclude that obesity negatively impacts the ability of DCs to mature and elicit appropriate T-cell responses to a general stimulus. This may contribute to the increased susceptibility to viral infection observed in severe obesity.

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Morbidly Obese Human Subjects Have Increased Peripheral Blood CD4+ T Cells With Skewing Toward a Treg- and Th2-Dominated Phenotype

Cited by 153 publications

References 52 publications

Lymphocytes in obesity-related adipose tissue inflammation

Lymphocytes in obesity-related adipose tissue inflammation

Increased fat cell size: a major phenotype of subcutaneous white adipose tissue in non-obese individuals with type 2 diabetes

Changes in human dendritic cell number and function in severe obesity may contribute to increased susceptibility to viral infection

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