A Novel Function of Adipocytes in Lipid Antigen Presentation to iNKT Cells

Abstract

Here, we demonstrated that iNKT cells were decreased in number in the adipose tissue of obese subjects. Interestingly, CD1d, a molecule involved in lipid antigen presentation to iNKT cells, was highly expressed in adipocytes, and CD1d-expressing adipocytes stimulated iNKT cell activity through physical interaction. iNKT cell population and CD1d expression were reduced in the adipose tissue of obese mice and humans compared to those of lean subjects. Moreover, iNKT cell-deficient J␣18 knockout mice became more obese and exhibited increased adipose tissue inflammation at the early stage of obesity. These data suggest that adipocytes regulate iNKT cell activity via CD1d and that the interaction between adipocytes and iNKT cells may modulate adipose tissue inflammation in obesity.

CD1d-mediated Presentation of Endogenous Lipid Antigens by Adipocytes Requires Microsomal Triglyceride Transfer Protein

“…IL2 release by iNKT DN32.D3 cells was also assessed, as this is a reported activity read-out. IL2 levels were very low without ␣GalCer stimulation in our coculture set-up (data not shown), as also reported by Huh et al (29), and therefore not analyzed in our subsequent experiments focusing on endogenous lipid antigen presentation. As a control, cytokine measurements were performed in the absence of iNKT cells, and only low concentrations were observed, which were not modulated by the addition of ␣GalCer (Fig.…”

“…2A), (ii) siRNA-mediated knockdown of PPAR␥ did not affect CD1d expression (Fig. 2B), and (iii) PPAR␥ activated the CD1d promoter only modestly in reporter assays (1.5-fold) (29). Taken together, this suggests that the increase in CD1d expression observed upon 24 h of treatment with the PPAR␥ ligand rosiglitazone (29) occurs through indirect mechanisms.…”

“…Taken together, this suggests that the increase in CD1d expression observed upon 24 h of treatment with the PPAR␥ ligand rosiglitazone (29) occurs through indirect mechanisms. Therefore, we would argue that C/EBP␤ and -␦ are required for the initial induction of CD1d expression during adipocyte differentiation, whereas the role of PPAR␥ is more likely to be indirect, analogous to the situation in dendritic cells (29,56).…”

“…This type of control ensures simultaneous expression of the key players required for endogenous lipid antigen presentation. Previously, several other transcription factors have been implicated in the regulation of CD1d expression in different cell types, including Ets family members (in hematopoietic cells) (55), retinoic acid receptor (in dendritic cells and mature adipocytes) (56), and PPAR␥ (in mature adipocytes) (29). However, we consider it unlikely that CD1d is under direct control of PPAR␥ during adipocyte differentiation as (i) we could not detect prominent PPAR␥ binding sites in a 200-kb chromosomal region surrounding the CD1d gene in mature adipocytes (41,42) or after short term stimulation (1 h) of mature 3T3-L1 adipocytes with the PPAR␥ ligand rosiglitazone (43) (Fig.…”

“…Recent studies showed the ability of iNKT cells to exert pathogenic and protective effects on AT function and metabolism (15-19, 24 -28). Interestingly, recent evidence suggests that adipocytes are able to present lipid antigens to iNKTs in a CD1d-dependent manner, and can therefore be considered non-professional lipid APCs (19,29). It is, however, not understood which proteins in adipocytes facilitate the CD1d lipidation and presentation pathway, and how regulation is established to produce and present lipid self-antigens in an immunogenic manner that stimulates T cell responses.…”