Format

Send to

Choose Destination
See comment in PubMed Commons below
J Immunol. 2014 Feb 15;192(4):1972-81. doi: 10.4049/jimmunol.1302623. Epub 2014 Jan 24.

α-Galactosylceramide but not phenyl-glycolipids induced NKT cell anergy and IL-33-mediated myeloid-derived suppressor cell accumulation via upregulation of egr2/3.

Author information

1
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan 11271;

Abstract

Strategies for cancer immunotherapy include activating immune system for therapeutic benefit or blockade of immune checkpoints. To harness innate immunity to fight cancer, α-galactosylceramide (α-GalCer) has been used to activate NKT cells. Unfortunately, administration of α-GalCer causes long-term NKT cell anergy, but the molecular mechanism is unclear. In this study, we showed that α-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 α-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, α-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, α-GalCer-induced FasL/TRAIL and IL-33 provided a novel mechanism underlying α-GalCer-induced hepatotoxicity and MDSC accumulation. In contrast, analogs of α-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 α-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 α-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.

PMID:
24465013
DOI:
10.4049/jimmunol.1302623
[Indexed for MEDLINE]
Free full text

Publication type, MeSH terms, Substances

Publication type

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Miscellaneous

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire
    Loading ...
    Support Center