alpha-Galactosylceramide Analogs with Weak Agonist Activity for Human iNKT Cells Define New Candidate Anti-Inflammatory Agents
SCIE
SCOPUS
- Title
- alpha-Galactosylceramide Analogs with Weak Agonist Activity for Human iNKT Cells Define New Candidate Anti-Inflammatory Agents
- Authors
- Bricard, Gabriel; Venkataswamy, Manjunatha M.; Yu, Karl O. A.; Im, Jin S.; Ndonye, Rachel M.; Howell, Amy R.; Veerapen, Natacha; Illarionov, Petr A.; Besra, Gurdyal S.; Li, Qian; Chang, Young-Tae; Porcelli, Steven A.
- Date Issued
- 2010-12
- Publisher
- PUBLIC LIBRARY SCIENCE
- Abstract
- CD1d-restricted natural killer T cells with invariant T cell receptor alpha chains (iNKT cells) are a unique lymphocyte subset that responds to recognition of specific lipid and glycolipid antigens. They are conserved between mice and humans and exert various immunoregulatory functions through their rapid secretion of a variety of cytokines and secondary activation of dendritic cells, B cells and NK cells. In the current study, we analyzed the range of functional activation states of human iNKT cells using a library of novel analogs of alpha-galactosylceramide (alpha GalCer), the prototypical iNKT cell antigen. Measurement of cytokines secreted by human iNKT cell clones over a wide range of glycolipid concentrations revealed that iNKT cell ligands could be classified into functional groups, correlating with weak versus strong agonistic activity. The findings established a hierarchy for induction of different cytokines, with thresholds for secretion being consistently lowest for IL-13, higher for interferon-gamma (IFN gamma), and even higher for IL-4. These findings suggested that human iNKT cells can be intrinsically polarized to selective production of IL-13 by maintaining a low level of activation using weak agonists, whereas selective polarization to IL-4 production cannot be achieved through modulating the strength of the activating ligand. In addition, using a newly designed in vitro system to assess the ability of human iNKT cells to transactivate NK cells, we found that robust secondary induction of interferon-gamma secretion by NK cells was associated with strong but not weak agonist ligands of iNKT cells. These results indicate that polarization of human iNKT cell responses to Th2-like or anti-inflammatory effects may best be achieved through selective induction of IL-13 and suggest potential discrepancies with findings from mouse models that may be important in designing iNKT cell-based therapies in humans.
- Keywords
- KILLER T-CELLS; INVARIANT NKT CELLS; CD1D MOLECULES; TUMOR IMMUNOSURVEILLANCE; ANTITUMOR CYTOTOXICITY; CUTTING EDGE; NOD MICE; ACTIVATION; RECOGNITION; ANTIGENS
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/50214
- DOI
- 10.1371/journal.pone.0014374
- ISSN
- 1932-6203
- Article Type
- Article
- Citation
- PLOS ONE, vol. 5, no. 12, 2010-12
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