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|Title:||α-Galactosylceramide Analogs with Weak Agonist Activity for Human iNKT Cells Define New Candidate Anti-Inflammatory Agents|
|Citation:||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. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0014374|
|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. © 2010 Bricard et al.|
|Source Title:||PLoS ONE|
|Appears in Collections:||Staff Publications|
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