Differential alteration of lipid antigen presentation to NKT cells due to imbalances in lipid metabolism

Abstract

Deficiencies in enzymes of the lysosomal glycosphingolipid degradation pathway or in lysosomal lipid transfer proteins cause an imbalance in lipid metabolism and induce accumulation of certain lipids. A possible impact of such an imbalance on the presentation of lipid antigens to lipid-reactive T cells has only been hypothesized but not extensively studied so far. Here we demonstrate that presentation of lipid antigens to, and development of, lipid-reactive CD1d-restricted NKT cells, are impaired in mice deficient in the lysosomal enzyme b-galactosidase (bGal) or the lysosomal lipid transfer protein Niemann-Pick C (NPC) 2. Importantly, the residual populations of NKT cells selected in bGal -/-and NPC2 -/-mice showed differential TCR and CD4 repertoire characteristics, suggesting that differential selecting CD1d:lipid antigen complexes are formed. Furthermore, we provide direct evidence that accumulation of lipids impairs lipid antigen presentation in both cases. However, the mechanisms by which imbalanced lipid metabolism affected lipid antigen presentation were different. Based on these results, the impact of lipid accumulation should be generally considered in the interpretation of immunological deficiencies found in mice suffering from lipid metabolic disorders.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2007/37160_s.pdf IntroductionDefects in lysosomal lipid trafficking or degradation result in a severe imbalance of lipid metabolism. Little is known about the consequences of such an imbalance on the presentation of lipid antigens to lipid-reactive T cells, e.g., the important immunoregulatory invariant (i) NKT cell subset (Va14i and Va24i NKT cells in mice and humans, respectively), which recognizes glycolipid antigens presented by the MHC class I-like molecule Abbreviations: a-GalCer: a-galactosylceramide (KRN7000) Á a/bGal: a/b-galactosidase Á DN: CD4 -CD8 -double negative Á DP: CD4 + CD8 + double positive Á Hex: hexosaminidase Á HSA: heat-stable Ag Á i: invariant Á iGb3: isoglobotrihexosylceramide Á NB-DNJ: N-butyldeoxynojirimycin Á NPC: NiemannPick C Eur. J. Immunol. 2007Immunol. . 37: 1431Immunol. -1441 CD1d. In mice, the TCR of Va14i NKT cells is composed of an invariant Va14-Ja18 chain, paired preferentially with a restricted b chain, mostly containing Vb8.2 or Vb7 (the human equivalents are Va24-Ja18 and Vb11) [1][2][3][4]. Va14i NKT cells are implicated in the regulation of antitumor immunity, antimicrobial responses, and the balance between tolerance and autoimmunity [5,6]. Va14i NKT cells, which can be either CD4 + or CD4 -CD8 -double negative (DN), are a thymus-dependent population derived from CD4 + CD8 + double-positive (DP) thymocytes [7][8][9][10][11]. Different maturation stages of developing thymic Va14i NKT cells have been described, characterized by the sequential acquisition of CD44 and NK1.1 in C57BL/6 mice [12][13][14]. Unlike conventional MHC-dependent T cells, Va14i NKT cells are not positively selected by thymic epithelial cell...

Dietary fatty acids modulate antigen presentation to hepatic NKT cells in nonalcoholic fatty liver disease

“…Previous study shows that diets containing high saturated or unsaturated fatty acids result in similar alterations in the phospholipid class distribution and fatty acid composition in the liver ( 28 ). It is known that lipid accumulation due to dysregulation of lipid metabolism can cause defective presentation of lipid antigens to NKT cells and impacts NKT cell accumulation ( 16 ). Little is known, however, about the effect of dietary fatty acids on CD1d-mediated NKT cell activation.…”

“…However, there is little knowledge about the mechanism by which dietary fatty acids regulate hepatic NKT cells. An earlier study has shown that imbalance in lipid metabolism can alter lipid antigen presentation to NKT cells ( 16 ).…”

Fine tuning by human CD1e of lipid-specific immune responses

“…Human CD1d-restricted type 1 and type 2 NKT, CD1b-restricted and CD1c-restricted T-cell clones, and mouse iNKT hybridomas were derived as described (21)(22)(23) and maintained according to standard procedures. Human monocytic THP-1 and C1R B cells were transfected with human CD1B, CD1C, and CD1D cDNAs alone or in combination with human CD1E cDNA, using the BCMGS-Neo and BCMGS-Hygro vectors (4).…”

Invariant NKT cells reduce the immunosuppressive activity of influenza A virus–induced myeloid-derived suppressor cells in mice and humans

“…To further investigate the mechanisms that control the crosstalk between iNKT cells and TLR-L-treated MDSCs, we used MDSCs derived from β-hexosaminidase A/Bdeficient (Hexβ -/-) mice, which are unable to activate iNKT cells due to the accumulation of glycosphingolipids (GSLs) in the endolysosomal compartment (48)(49)(50). We showed that the crosstalk between iNKT cells and CpG- or poly I:C-treated MDSCs is compromised in GSL storage disorders ( Figure 5, A and B), although TLR-L incubation of Hexβ -/-derived MDSCs upregulates CD1d expression and results in enhanced IL-12 secretion (Supplemental Figure 5).…”