T Cell Populations and Functions Are Altered in Human Obesity and Type 2 Diabetes
- 596 Downloads
Purpose of the Review
Obesity and type 2 diabetes (T2D) are considered chronic inflammatory diseases. While early publications have reported the implication of innate immune cells such as macrophages to promote systemic inflammation and metabolic dysfunctions, recent publications underline the alterations of the T cell compartment in human obesity and type 2 diabetes. These recent findings are the focus of this review.
In humans, obesity and T2D induce the expansion of proinflammatory T cells such as CD4 Th1, Th17, and CD8 populations, whereas innate T cells such as MAIT and iNKT cells are decreased. These alterations reflect a loss of total T cell homeostasis that may contribute to tissue and systemic inflammation.
Whether these changes are adaptive to nutritional variations and/or contribute to the progression of metabolic diseases remains to be clarified. T cell phenotyping may improve obese and/or T2D patient stratification with therapeutic and prognostic implications.
KeywordsObesity Type 2 diabetes Inflammation T cell Th17 MAIT
The laboratory is supported by the European Union’s Seventh Framework Program for research, technological development and demonstration under grant agreement HEALTH-F4-2012-305312 (METACARDIS), the French National Agency of Research (ANR-2014 OBE-MAIT and ADIPOFIB), and French Foundation for Medical Research. Assistance Publique-Hôpitaux de Paris (APHP) is the promoter of the clinical investigations performed at the Human Research Nutrition Center by the authors mentioned in this review. The authors would like to thank Timothy Swartz (Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris) for manuscript language editing.
Compliance with Ethical Standards
Conflict of Interest
Sothea Touch, Karine Clément, and Sébastien André declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article describes results from studies with human subjects performed by the three authors. All reported studies have been previously published. An informed consent was obtained for all subjects. The Ethics Committee (Comité de protection des personnes, CPP Ile-de-France) approved the studies, which were conducted in accordance with the Helsinki Declaration and are registered in clinical trials. This article does not contain any studies with animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 5.Dalmas E, Rouault C, Abdennour M, Rovere C, Rizkalla S, Bar-Hen A, et al. Variations in circulating inflammatory factors are related to changes in calorie and carbohydrate intakes early in the course of surgery-induced weight reduction. Am J Clin Nutr. 2011;94(2):450–8. doi: 10.3945/ajcn.111.013771.CrossRefPubMedGoogle Scholar
- 13.Duffaut C, Zakaroff-Girard A, Bourlier V, Decaunes P, Maumus M, Chiotasso P, et al. Interplay between human adipocytes and T lymphocytes in obesity: CCL20 as an adipochemokine and T lymphocytes as lipogenic modulators. Arterioscler Thromb Vasc Biol. 2009;29(10):1608–14. doi: 10.1161/ATVBAHA.109.192583.CrossRefPubMedGoogle Scholar
- 15.•• Monteiro-Sepulveda M, Touch S, Mendes-Sá C, André S, Poitou C, Allatif O, et al. Jejunal T cell inflammation in human obesity correlates with decreased enterocyte insulin signaling. Cell Metab. 2015;22(1):113–24. doi: 10.1016/j.cmet.2015.05.020. This work explores for the first time in a large cohort of obese and diabetic patients compared to lean individuals the phenotype of immune cells and notably T cells and their impact on enterocyte insulin sensitivity.CrossRefPubMedGoogle Scholar
- 16.Kintscher U, Hartge M, Hess K, Foryst-Ludwig A, Clemenz M, Wabitsch M, et al. T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Arterioscler Thromb Vasc Biol. 2008;28(7):1304–10. doi: 10.1161/ATVBAHA.108.165100.CrossRefPubMedGoogle Scholar
- 20.McLaughlin T, Liu L-F, Lamendola C, Shen L, Morton J, Rivas H, et al. T-cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans. Arterioscler Thromb Vasc Biol. 2014;34(12):2637–43. doi: 10.1161/ATVBAHA.114.304636.CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Jagannathan-Bogdan M, McDonnell ME, Shin H, Rehman Q, Hasturk H, Apovian CM, et al. Elevated proinflammatory cytokine production by a skewed T cell compartment requires monocytes and promotes inflammation in type 2 diabetes. J Immunol. 2011;186(2):1162–72. doi: 10.4049/jimmunol.1002615.CrossRefPubMedGoogle Scholar
- 27.Sumarac-Dumanovic M, Jeremic D, Pantovic A, Janjetovic K, Stamenkovic-Pejkovic D, Cvijovic G, et al. Therapeutic improvement of glucoregulation in newly diagnosed type 2 diabetes patients is associated with a reduction of IL-17 levels. Immunobiology. 2013;218(8):1113–8. doi: 10.1016/j.imbio.2013.03.002.CrossRefPubMedGoogle Scholar
- 28.• Zhao R, Tang D, Yi S, Li W, Wu C, Lu Y, et al. Elevated peripheral frequencies of Th22 cells: a novel potent participant in obesity and type 2 diabetes. PLoS One. 2014;9(1):e85770. doi: 10.1371/journal.pone.0085770. One of the first studies exploring Th22 subset and cytokine production in the blood of obese and type 2 diabetic patients.CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Bertola A, Ciucci T, Rousseau D, Bourlier V, Duffaut C, Bonnafous S, et al. Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing Th17 responses in mice and patients. Diabetes. 2012;61(9):2238–47. doi: 10.2337/db11-1274.CrossRefPubMedPubMedCentralGoogle Scholar
- 31.•• Dalmas E, Venteclef N, Caer C, Poitou C, Cremer I, Aron-Wisnewsky J, et al. T cell-derived IL-22 amplifies IL-1β-driven inflammation in human adipose tissue: relevance to obesity and type 2 diabetes. Diabetes. 2014;63(6):1966–77. doi: 10.2337/db13-1511. This paper provides new insights into the dialogue between macrophages and T cells through the secretions of IL-1β and Th17-derived cytokines in the obese adipose tissue.CrossRefPubMedGoogle Scholar
- 37.van der Weerd K, Dik WA, Schrijver B, Schweitzer DH, Langerak AW, Drexhage HA, et al. Morbidly obese human subjects have increased peripheral blood CD4+ T cells with skewing toward a Treg- and Th2-dominated phenotype. Diabetes. 2012;61(2):401–8. doi: 10.2337/db11-1065.CrossRefPubMedPubMedCentralGoogle Scholar
- 40.Pereira S, Teixeira L, Aguilar E, Oliveira M, Savassi-Rocha A, Pelaez JN, et al. Modulation of adipose tissue inflammation by FOXP3+ Treg cells, IL-10, and TGF-β in metabolically healthy class III obese individuals. Nutrition. 2014;30(7–8):784–90. doi: 10.1016/j.nut.2013.11.023.CrossRefPubMedGoogle Scholar
- 47.Lynch L, Nowak M, Varghese B, Clark J, Hogan AE, Toxavidis V, et al. Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. Immunity. 2012;37(3):574–87. doi: 10.1016/j.immuni.2012.06.016.CrossRefPubMedPubMedCentralGoogle Scholar
- 51.• Carolan E, Tobin LM, Mangan BA, Corrigan M, Gaoatswe G, Byrne G, et al. Altered distribution and increased IL-17 production by mucosal-associated invariant T cells in adult and childhood obesity. J Immunol. 2015;194(12):5775–80. doi: 10.4049/jimmunol.1402945. This is the first study exploring MAIT cells frequency in the adipose tissue of obese versus lean subjects; the authors show that MAIT cell frequency is decreased in the obese adipose tissue.CrossRefPubMedGoogle Scholar
- 52.•• Magalhaes I, Pingris K, Poitou C, Bessoles S, Venteclef N, Kiaf B, et al. Mucosal-associated invariant T cell alterations in obese and type 2 diabetic patients. J Clin Invest. 2015;125(4):1752–62. doi: 10.1172/JCI78941. This paper reports that circulating MAIT cells are decreased in obesity and type 2 diabetic subjects with increased proinflammatory cytokine production.CrossRefPubMedPubMedCentralGoogle Scholar
- 63.Hiejima E, Kawai T, Nakase H, Tsuruyama T, Morimoto T, Yasumi T, et al. Reduced numbers and Proapoptotic features of mucosal-associated invariant T cells as a characteristic finding in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2015;21(7):1529–40. doi: 10.1097/MIB.0000000000000397.CrossRefPubMedGoogle Scholar
- 69.Costanzo AE, Taylor KR, Dutt S, Han PP, Fujioka K, Jameson JM. Obesity impairs γδ T cell homeostasis and antiviral function in humans. PLoS One. 2015;10(3) doi: 10.1371/journal.pone.0120918.
- 73.Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol. 2011;12(4):295–303. doi: 10.1038/ni.2005.CrossRefPubMedPubMedCentralGoogle Scholar