Figure 3.

Modes of NKT and MAIT cell activation by microbes. Potent agonists—such as αGalCer, directly activate NKT cells, without the need for a second signal, in a TCR signaling–dominated fashion (left panel). Alternatively, microbes containing TLR ligands such as LPS activate NKT cells by inducing IL-12 production by DCs, which amplifies weak responses elicited upon the recognition of CD1d bound with self-glycolipids by the NKT cell TCR. Several endogenous lipid agonists have been identified and characterized (see Table 1 ). Some microbes—such as Sphingomonas capsulata and Borrelia burgdorferi—synthesize α-anomeric glycolipids for their cell walls. These glycolipids, when presented by CD1d, weakly activate NKT cells directly. In the presence of a second signal—generally a proinflammatory cytokine such as IL-12, such weak agonists strongly activate NKT cells (middle panel). By contrast, the mode of MAIT cell activation appears to be agonist concentration dependent: microbes that produce high levels of 5-OP-RU—a product of ribD-controlled catalytic activity, directly activate MAIT cells, while those that produce low levels of 5-OP-RU require a cytokine boost. Unlike conventional T cells, cytokines alone can activate both NKT and MAIT cells. Such cytokines, which include a combination of IL-12 and IL-18, activate NKT cells in a TCR-independent manner (right panel). This diagram renders the different strategies for NKT cell activation; they apply to MAIT cells as well. Similarities and differences, if any, are described in the text. Adapted from past reviews (35, 37, 38, 41) and works cited in the text.