| First Author | Huang JR | Year | 2014 |
| Journal | J Immunol | Volume | 192 |
| Issue | 4 | Pages | 1972-81 |
| PubMed ID | 24465013 | Mgi Jnum | J:209438 |
| Mgi Id | MGI:5567864 | Doi | 10.4049/jimmunol.1302623 |
| Citation | Huang JR, et al. (2014) alpha-Galactosylceramide but not phenyl-glycolipids induced NKT cell anergy and IL-33-mediated myeloid-derived suppressor cell accumulation via upregulation of egr2/3. J Immunol 192(4):1972-81 |
| abstractText | Strategies for cancer immunotherapy include activating immune system for therapeutic benefit or blockade of immune checkpoints. To harness innate immunity to fight cancer, alpha-galactosylceramide (alpha-GalCer) has been used to activate NKT cells. Unfortunately, administration of alpha-GalCer causes long-term NKT cell anergy, but the molecular mechanism is unclear. In this study, we showed that alpha-GalCer-triggered egr2/3, which induced programmed death 1 and cbl-b in NKT cells, leading to NKT cell anergy. We also uncovered the induction of the immunosuppressive myeloid-derived suppressor cells (MDSCs) in the spleen by alpha-GalCer that might attenuate its antitumor efficacy. The accumulation of MDSC was accompanied by 20-fold rise in their arg-1 mRNAs and enhanced expression of programmed death 1/programmed death ligand 1. Furthermore, alpha-GalCer-induced egr-2/3 in hepatic NKT cells upregulated their TRAIL in addition to Fas ligand (FasL) and induced alarm signaling molecule IL-33 in Kupffer cells, presumably because of liver damage triggered by TRAIL/FasL. We further demonstrated that IL-33-stimulated macrophages produce G-CSF, which in turn, boosted MDSCs. Thus, alpha-GalCer-induced FasL/TRAIL and IL-33 provided a novel mechanism underlying alpha-GalCer-induced hepatotoxicity and MDSC accumulation. In contrast, analogs of alpha-GalCer containing phenyl group in the lipid tail could neither induce NKT anergy nor enhance MDSCs accumulation. Furthermore, tumor-infiltrating MDSCs in mice injected repeatedly with alpha-GalCer were 2-fold higher than those treated with phenyl-glycolipids. These results not only revealed the induction of MDSC via IL-33 as a new mechanism for alpha-GalCer-elicited immunosuppression but also provided one of the mechanisms underlying the superior antitumor potency of phenyl-glycolipids. Our findings have important implications for the development of NKT-stimulatory glycolipids as vaccine adjuvants and anticancer therapeutics. |
