Harnessing invariant natural killer T cells to control pathological inflammation

Invariant natural killer T (iNKT) cells are innate T cells that are recognized for their potent immune modulatory functions. Over the last three decades, research in murine models and human observational studies have revealed that iNKT cells can act to limit inflammatory pathology in a variety of settings. Since iNKT cells are multi-functional and can promote inflammation in some contexts, understanding the mechanistic basis for their anti-inflammatory effects is critical for effectively harnessing them for clinical use. Two contrasting mechanisms have emerged to explain the anti-inflammatory activity of iNKT cells: that they drive suppressive pathways mediated by other regulatory cells, and that they may cytolytically eliminate antigen presenting cells that promote excessive inflammatory responses. How these activities are controlled and separated from their pro-inflammatory functions remains a central question. Murine iNKT cells can be divided into four functional lineages that have either pro-inflammatory (NKT1, NKT17) or anti-inflammatory (NKT2, NKT10) cytokine profiles. However, in humans these subsets are not clearly evident, and instead most iNKT cells that are CD4⁺ appear oriented towards polyfunctional (T_H0) cytokine production, while CD4^- iNKT cells appear more predisposed towards cytolytic activity. Additionally, structurally distinct antigens have been shown to induce T_H1- or T_H2-biased responses by iNKT cells in murine models, but human iNKT cells may respond to differing levels of TCR stimulation in a way that does not neatly separate T_H1 and T_H2 cytokine production. We discuss the implications of these differences for translational efforts focused on the anti-inflammatory activity of iNKT cells.