Abstract
CD1d-restricted natural killer T cells with invariant T cell receptor α 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 (IFNγ), 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.
Highlights
Natural killer T cells (NKT cells) were originally defined as T cells that constitutively expressed NK-associated receptors in naıve mice [1,2,3,4]
Identification of strong and weak glycolipid agonists for human iNKT cells To characterize the quality of human iNKT cell responses to KRN7000 and to identify potential Th1 or Th2 skewing analogs, we assessed the reactivity of human iNKT cell clones to KRN7000 and multiple aGalCer analogs
Since full activation of iNKT cells has been reported to occur in the context of autoreactivity and costimulation with IL-12 plus IL-18 [13;15], we examined the effect of these two cytokines on the responses to weak agonist glycolipids or suboptimal doses of strong agonists
Summary
Natural killer T cells (NKT cells) were originally defined as T cells that constitutively expressed NK-associated receptors in naıve mice [1,2,3,4]. INKT cells have a striking capacity to concurrently produce cytokines that are classically associated with both Th1 responses (e.g., IFNc, TNFa) and Th2 responses (IL-4, IL-5, IL-13) Their activation leads to induction of DC maturation, transactivation of NK cells and help to B cells [1;10]. Additional physiological functions of iNKT cells have been defined recently based on the fact that iNKT cells show a weak and CD1d-dependent reactivity to self lipid(s) ( referred to as ‘‘autoreactivity’’). This is especially characterized by IL-13 and GM-CSF secretion, as shown most clearly for human iNKT cells upon coculture with monocytes [13] and DCs [14]. In the context of microbial infection, a higher degree of iNKT cell activation is achieved upon self-lipid recognition together with APC-derived IL-12 and IL-18, or type I Interferon co-stimulation, leading to a strong IFNc production [13;15;16]
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