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

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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 - 2010

Fingerprint

Galactosylceramides
anti-inflammatory agents
Natural Killer T-Cells
Interleukin-13
Human Activities
agonists
Anti-Inflammatory Agents
Chemical activation
Glycolipids
Cytokines
Ligands
Interleukin-4
Interferons
Clone cells
Polarization
natural killer cells
Antigens
T-cells
Lymphocytes
cells

ASJC Scopus subject areas

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

Cite this

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

In: PLoS One, Vol. 5, No. 12, e14374, 2010, p. 1-16.

Research output: Contribution to journalArticle

Bricard, G, Venkataswamy, MM, Yu, KOA, Im, JS, Ndonye, RM, Howell, AR, Veerapen, N, Illarionov, PA, Besra, GS, Li, Q, Chang, YT & Porcelli, SA 2010, 'α-Galactosylceramide Analogs with Weak Agonist Activity for Human iNKT Cells Define New Candidate Anti-Inflammatory Agents', PLoS One, vol. 5, no. 12, e14374, pp. 1-16. https://doi.org/10.1371/journal.pone.0014374
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. / α-Galactosylceramide Analogs with Weak Agonist Activity for Human iNKT Cells Define New Candidate Anti-Inflammatory Agents. In: PLoS One. 2010 ; Vol. 5, No. 12. pp. 1-16.
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