Figure 2.

Mechanisms of mucosal-associated invariant T (MAIT) cell and invariant natural killer T (iNKT) cell activation. MAIT cells and iNKT cells are activated via three main pathways: T cell receptor (TCR)-dependent (A), TCR-independent (predominantly cytokine-driven) (B), and combined TCR-dependent and -independent (C). (A) In response to TCR signaling, MAIT cells and iNKT cells produce cytokines and exhibit cytotoxic activity. The degree of activation is modulated by costimulatory molecules, including CD161. The array of cytokines produced by iNKT cells varies upon activation of different costimulatory pathways. Whether this is also the case for MAIT cells is currently unknown. (B) TCR-independent activation is largely cytokine-mediated, with similar combinations of cytokines capable of activating both MAIT cells and iNKT cells, for example, IL-12 + IL-18. However, while IL-12 (bold) appears dominant for iNKT cell activation, IL-18 (bold) is key for MAIT cells. Cytokine-dependent activation of MAIT and iNKT cells may require prior TCR stimulation, as has been reported for human iNKT cells. As well as by cytokines, iNKT cells can be directly activated via certain natural killer (NK) cell receptors, such as NK1.1 in mice. IFN-γ production may predominate following TCR-independent activation, although this requires further investigation. (C) MAIT cells and iNKT cells can be activated through a combination of TCR and cytokine signaling. In this setting, iNKT cell antigens are typically weak self-antigens (bold), but endogenous ligands for MAIT cells have not been identified.