α-Galactosylceramide Analogs with Weak Agonist Activity for Human iNKT Cells Define New Candidate Anti-Inflammatory Agents

Gabriel Bricard, Manjunatha M. Venkataswamy, Karl O.A. Yu, Jin S. Im, Rachel M. Ndonye, Amy R. Howell, Natacha Veerapen, Petr A. Illarionov, Gurdyal S. Besra, Qian Li, Young Tae Chang, Steven A. Porcelli

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

CD1d-restricted natural killer T cells with invariant T cell receptor a 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 α-galactosylceramide (αGalCer), 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-γ (IFNc), 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-γ 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.

Original languageEnglish (US)
Article numbere14374
Pages (from-to)1-16
Number of pages16
JournalPloS one
Volume5
Issue number12
DOIs
StatePublished - Dec 1 2010

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Bricard, G., Venkataswamy, M. M., Yu, K. O. A., Im, J. S., Ndonye, R. M., Howell, A. R., Veerapen, N., Illarionov, P. A., Besra, G. S., Li, Q., Chang, Y. T., & Porcelli, S. A. (2010). α-Galactosylceramide Analogs with Weak Agonist Activity for Human iNKT Cells Define New Candidate Anti-Inflammatory Agents. PloS one, 5(12), 1-16. [e14374]. https://doi.org/10.1371/journal.pone.0014374