NKT cell costimulation: experimental progress and therapeutic promise

Abstract

Invariant natural killer T (iNKT) cells are innate lymphocytes with unique specificity for glycolipid antigens and remarkable immunomodulatory properties. The role of costimulatory interactions in iNKT cell responses has recently come under scrutiny. Although iNKT cells and their prototype glycolipid agonist α-galactosylceramide (α-GalCer) have shown promise in several clinical trials conducted in patients with cancer or viral diseases, current iNKT cell-based therapies are far from effective. The concomitant targeting of T cell receptors (TCRs) and costimulatory molecules on iNKT cells represents an exciting new opportunity to optimize such therapeutic approaches. Here, we review recent advances in our understanding of iNKT cell costimulation and discuss potential treatment modalities based on the responsiveness of iNKT cells to disease-tailored glycolipids and select costimulatory ligands.

Figure 1

Costimulatory and coinhibitory interactions between iNKT cells and APCs. iNKT cells recognize and respond to glycolipid antigens (e.g. α-GalCer) presented in the context of CD1d expressed by APCs. These responses are regulated by several costimulatory (green) and coinhibitory (red) molecules belonging to the Ig superfamily, the TNFR/TNF superfamily or the TIM family (a). Cell surface molecules represented in brown have yet to be firmly classified as costimulatory or coinhibitory in iNKT cell responses. For instance, the expression and function of CTLA-4 in iNKT cells have not been established. Costimulatory interactions affect T_H1- and/or T_H2-type cytokine production by iNKT cells. These interactions might also mediate crosstalk between iNKT cells and DC subsets (b). TLR-9 triggering by CpG-ODNs stimulates pDCs to produce type I IFN. This effect together with the OX40–OX40L interaction contributed by pDCs synergizes with an iTCR signal to promote IFN-γ production by iNKT cells [66]. The iTCR signal is dependent on α-GalCer presentation by conventional DCs (cDCs) to iNKT cells. This signal also leads to CD40L upregulation in iNKT cells, which engages with CD40 in cDCs and stimulates their IL-12 secretion and enhanced B7 expression [59,61]. IL-12 and CD28–B7 interactions in turn act on iNKT cells and modulate their cytokine responses. Infection with viral pathogens such as LCMV might result in the enhanced expression of OX40 in iNKT cells [63]. This represents yet another mechanism by which the OX40–OX40L-mediated interaction between iNKT cells and pDCs can stimulate type I IFN secretion by pDCs. Ultimately, this three-way communication results in a T_H1-type iNKT cell response.