Adipose Tissue Invariant NKT Cells Protect against Diet-Induced Obesity and Metabolic Disorder through Regulatory Cytokine Production

Lynch, Lydia; Nowak, Michael A.; Varghese, Bindu; Clark, Justice; Hogan, Andrew E.; Toxavidis, Vasillis; Balk, Steven P.; O’Shea, Donal; O’Farrelly, Cliona; Exley, Mark A.

doi:10.1016/j.immuni.2012.06.016

Cited by 416 publications

(541 citation statements)

References 58 publications

Supporting

Mentioning

514

Contrasting

Unclassified

Order By: Relevance

“…Although the pathological impact of both innate and adaptive immune cells, including myeloid cells, B cells, T cells, and natural killer T (NKT) cells, has been documented in DIO models (1,7,9,11,12,28,29), the molecular signaling pathways that mediate their effects remain largely unexplored and unclear. In the present study, we have identified the transcription factor Stat3 as an important mediator of T-cell-driven inflammation in adipose tissue of DIO mice.…”

Section: Discussionmentioning

confidence: 99%

Regulation of adipose tissue T cell subsets by Stat3 is crucial for diet-induced obesity and insulin resistance

Priceman¹,

Kujawski²,

Shen³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

104

View full text Add to dashboard Cite

Dysregulated inflammation in adipose tissue, marked by increased proinflammatory T-cell accumulation and reduced regulatory T cells (Tregs), contributes to obesity-associated insulin resistance. The molecular mechanisms underlying T-cell-mediated inflammation in adipose tissue remain largely unknown, however. Here we show a crucial role for signal transducer and activator of transcription 3 (Stat3) in T cells in skewing adaptive immunity in visceral adipose tissue (VAT), thereby contributing to diet-induced obesity (DIO) and insulin resistance. Stat3 activity is elevated in obese VAT and in VAT-resident T cells. Functional ablation of Stat3 in T cells reduces DIO, improves insulin sensitivity and glucose tolerance, and suppresses VAT inflammation. Importantly, Stat3 ablation reverses the high Th1/Treg ratio in VAT of DIO mice that is likely secondary to elevated IL-6 production, leading in turn to suppression of Tregs. In addition, Stat3 in T cells in DIO mice affects adipose tissue macrophage accumulation and M2 phenotype. Our study identifies Stat3 in VAT-resident T cells as an important mediator and direct target for regulating adipose tissue inflammation, DIO, and its associated metabolic dysfunctions.

show abstract

Section: Discussionmentioning

confidence: 99%

Regulation of adipose tissue T cell subsets by Stat3 is crucial for diet-induced obesity and insulin resistance

Priceman¹,

Kujawski²,

Shen³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

104

View full text Add to dashboard Cite

show abstract

“…For example, adipose tissue is immunologically active and obesity causes a sterile inflammation80 in which iNKT may play an immunoregulatory role 81, 82. MAIT cells may contribute to this inflammation because in human obesity they are enriched in adipose tissue compared with blood, and have a shift towards higher IL‐17 production and reduced IL‐10 secretion 82, 83.…”

Section: Observations From Specific Diseasesmentioning

confidence: 99%

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

2016

View full text Add to dashboard Cite

SummaryMucosal‐associated invariant T (MAIT) cells are a novel class of innate‐like T cells, expressing a semi‐invariant T‐cell receptor (TCR) and able to recognize small molecules presented on the non‐polymorphic MHC‐related protein 1. Their intrinsic effector‐memory phenotype, enabling secretion of pro‐inflammatory cytokines, and their relative abundance in humans imply a significant potential to contribute to autoimmune processes. However, as MAIT cells were unknown until recently and specific immunological tools were unavailable, little is known of their roles in disease. Here I review observations from clinical studies and animal models of autoimmune and immune‐mediated diseases including the roles of MAIT cells in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and airways diseases. MAIT cell deficiencies are frequently observed in peripheral blood, and at sites of disease such as the airways in asthma. However, MAIT cells have a specific sensitivity to suppression by therapeutic corticosteroids that may confound many of these observations, as may the tendency of the surface marker CD161 to activation‐induced down‐regulation. Nonetheless, the dependence on bacteria for the development of MAIT cells suggests a potentially important protective role linking the influences of early life microbial exposures and subsequent development of autoimmunity. Conversely, MAIT cells could contribute to chronic inflammation either through TCR‐independent activation, or potentially by TCR recognition of as yet undiscovered ligands. Future research will be greatly facilitated by the immunological tools that are now available, including murine genetic models and human and murine specific tetramers.

show abstract

“…iNKT cells resident in AT are also a major source of IL-4. Compared with their peripheral counterparts, AT-resident iNKT cells express higher levels of IL-4 and IL-10, and CD1d-deficient mice, which cannot present lipid antigen to iNKT cells, develop spontaneous obesity even when fed a low-fat diet (13).…”

Section: Immune Cell Composition In Lean Atmentioning

confidence: 99%

Obesity-Associated Adipose Tissue Inflammation and Transplantation

Wu¹,

Dawson²,

Levings³

2016

American Journal of Transplantation

View full text Add to dashboard Cite

Obesity is often associated with the development of adipose tissue (AT) inflammation, resulting in metabolic dysfunction and an increased risk for developing type 2 diabetes. It is also associated with multiple chronic diseases, including cardiovascular, liver, and kidney disease, and thus can contribute to organ failure. Several studies have investigated whether there is a correlation between obesity and outcomes in transplantation, but there is currently very limited information on the specific role of AT inflammation in the rejection process or on the overall function of the transplanted organ. Here, we provide a brief review of the current understanding of the cellular mechanisms that control obesity-associated AT inflammation and summarize knowledge about how obesity affects clinical outcomes following solid organ or hematopoietic stem cell transplantation. We also highlight opportunities for more research to better understand how obesity affects outcomes of transplantation.

show abstract

Adipose Tissue Invariant NKT Cells Protect against Diet-Induced Obesity and Metabolic Disorder through Regulatory Cytokine Production

Cited by 416 publications

References 58 publications

Regulation of adipose tissue T cell subsets by Stat3 is crucial for diet-induced obesity and insulin resistance

Regulation of adipose tissue T cell subsets by Stat3 is crucial for diet-induced obesity and insulin resistance

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

Obesity-Associated Adipose Tissue Inflammation and Transplantation

Contact Info

Product

Resources

About