TCRα-TCRβ pairing controls recognition of CD1d and directs the development of adipose NKT cells

Vieth, Joshua A.; Das, Joy; Ranaivoson, F.M.; Comoletti, Davide; Denzin, Lisa K.; Sant’Angelo, Derek B.

doi:10.1038/ni.3622

Cited by 31 publications

(28 citation statements)

References 30 publications

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“…Macrophages and T cells were also increased in numbers in starch-oleate adipose tissue, possibly as a result of recruitment downstream of NK cell activation and infiltration 34, 35. Our experiments did not specifically interrogate for adipose-resident invariant NK T cells, which have been reported to have a unique phenotype 36, 37…”

Section: Discussionmentioning

confidence: 88%

Specific Macronutrients Exert Unique Influences on the Adipose-Liver Axis to Promote Hepatic Steatosis in Mice

Duwaerts

Amin

Siao

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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Background & AimsThe factors that distinguish metabolically healthy obesity from metabolically unhealthy obesity are not well understood. Diet has been implicated as a determinant of the unhealthy obesity phenotype, but which aspects of the diet induce dysmetabolism are unknown. The goal of this study was to investigate whether specific macronutrients or macronutrient combinations provoke dysmetabolism in the context of isocaloric, high-energy diets.MethodsMice were fed 4 high-energy diets identical in calorie and nutrient content but different in nutrient composition for 3 weeks to 6 months. The test diets contained 42% carbohydrate (sucrose or starch) and 42% fat (oleate or palmitate). Weight and glucose tolerance were monitored; blood and tissues were collected for histology, gene expression, and immunophenotyping.ResultsMice gained weight on all 4 test diets but differed significantly in other metabolic outcomes. Animals fed the starch-oleate diet developed more severe hepatic steatosis than those on other formulas. Stable isotope incorporation showed that the excess hepatic steatosis in starch-oleate–fed mice derived from exaggerated adipose tissue lipolysis. In these mice, adipose tissue lipolysis coincided with adipocyte necrosis and inflammation. Notably, the liver and adipose tissue abnormalities provoked by starch-oleate feeding were reproduced when mice were fed a mixed-nutrient Western diet with 42% carbohydrate and 42% fat.ConclusionsThe macronutrient composition of the diet exerts a significant influence on metabolic outcome, independent of calories and nutrient proportions. Starch-oleate appears to cause hepatic steatosis by inducing progressive adipose tissue injury. Starch-oleate phenocopies the effect of a Western diet; consequently, it may provide clues to the mechanism whereby specific nutrients cause metabolically unhealthy obesity.

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Section: Discussionmentioning

confidence: 88%

Specific Macronutrients Exert Unique Influences on the Adipose-Liver Axis to Promote Hepatic Steatosis in Mice

Duwaerts

Amin

Siao

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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“…A local instruction of the iNKT cell phenotype in polyps was also suggested by the fact that transfer of liver iNKT cells, that were predominantly iNKT1 (data not shown), to Apc Min/+J α 18 − / − mice reconstituted the polyp macrophage skewing towards M2 similar to what was found in Apc Min/+J α 18+/ − mice. A different scenario was proposed in a recent publication demonstrating that unique features of the TCR could determine the development of iNKT cells with a phenotype of adipose iNKT cells in the thymus, followed by subsequent accumulation of these iNKT cells in adipose tissue 46 . It remains to be investigated to what extent the tissue microenvironment induces the polyp iNKT-P neg or adipose tissue phenotype of iNKT cells, and which signals may be required for the development of these unusual iNKT cell phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Unique invariant natural killer T cells promote intestinal polyps by suppressing TH1 immunity and promoting regulatory T cells

et al. 2018

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CD1d-restricted invariant natural killer T (iNKT) cells are known as potent early regulatory cells of immune responses. Besides the established roles in the regulation of inflammation and autoimmune disease, studies have shown that iNKT cells have important roles in tumor surveillance and the control of tumor metastasis. Here we found that absence of iNKT cells dramatically decreased the total number of intestinal polyps in APCMin/+ mice, a model for colorectal cancer. Polyp iNKT cells were enriched for IL-10 and IL-17 producing cells, showed a distinct phenotype being CD4+, NK1.1− CD44int and PD-1lo, and they were negative for the NKT cell transcription factor PLZF. Absence of iNKT cells was associated with a reduced frequency of Treg cells and lower expression levels of FoxP3 protein and transcript uniquely in the polyps, and a switch to an inflammatory macrophage phenotype. Moreover, in iNKT cell deficient APCMin/+ mice, expression of T helper (TH) 1-associated genes, such as IFN-γ and Nos2, was increased in polyps, concomitantly with elevated frequencies of conventional CD4+ and CD8+ T cells in this tissue. The results suggest that a population of regulatory iNKT cells locally promote intestinal polyp formation by enhancing Treg cells and immunosuppression of anti-tumor TH1-immunity.

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“…Compared with other iNKT cells, AT‐resident iNKT cells express a distinct transcription factor profile, with high E4BP4 expression and low levels of promyelocytic leukemia zinc finger (PLZF), which underlies their anti‐inflammatory phenotype in lean AT . Interestingly, mutation of a hydrophobic patch that is formed upon pairing of the TCR‐ α and TCR‐ β on iNKT cells is sufficient to elicit an AT phenotype . In addition, experiments with endogenous and synthetic lipid antigens suggest that the identity of the lipid antigen can determine which cytokines are produced as well as the strength of the activation .…”

Section: Adipocyte–inkt Cell Interplay: Future Directionsmentioning

confidence: 99%

“…[76][77][78] Interestingly, mutation of a hydrophobic patch that is formed upon pairing of the TCR-a and TCR-b on iNKT cells is sufficient to elicit an AT phenotype. 80 In addition, experiments with endogenous and synthetic lipid antigens suggest that the identity of the lipid antigen can determine which cytokines are produced as well as the strength of the activation. 81,82 Together, these findings suggest that the tissue environment, i.e.…”

Section: Cd1d Loading and Presentationmentioning

confidence: 99%

Endogenous lipid antigens for invariant natural killer T cells hold the reins in adipose tissue homeostasis

et al. 2017

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The global obesity epidemic and its associated co-morbidities, including type 2 diabetes, cardiovascular disease and certain types of cancers, have drawn attention to the pivotal role of adipocytes in health and disease. Besides their 'classical' function in energy storage and release, adipocytes interact with adipose-tissue-resident immune cells, among which are lipid-responsive invariant natural killer T (iNKT) cells. The iNKT cells are activated by lipid antigens presented by antigen-presenting cells as CD1d/lipid complexes. Upon activation, iNKT cells can rapidly secrete soluble mediators that either promote or oppose inflammation. In lean adipose tissue, iNKT cells elicit a predominantly anti-inflammatory immune response, whereas obesity is associated with declining iNKT cell numbers. Recent work showed that adipocytes act as non-professional antigen-presenting cells for lipid antigens. Here, we discuss endogenous lipid antigen processing and presentation by adipocytes, and speculate on how these lipid antigens, together with 'environmental factors' such as tissue/organ environment and co-stimulatory signals, are able to influence the fate of adipose-tissue-resident iNKT cells, and thereby the role of these cells in obesity and its associated pathologies.

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TCRα-TCRβ pairing controls recognition of CD1d and directs the development of adipose NKT cells

Cited by 31 publications

References 30 publications

Specific Macronutrients Exert Unique Influences on the Adipose-Liver Axis to Promote Hepatic Steatosis in Mice

Specific Macronutrients Exert Unique Influences on the Adipose-Liver Axis to Promote Hepatic Steatosis in Mice

Unique invariant natural killer T cells promote intestinal polyps by suppressing TH1 immunity and promoting regulatory T cells

Endogenous lipid antigens for invariant natural killer T cells hold the reins in adipose tissue homeostasis

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