Invariant Natural Killer T‐Cell Receptors Bridge Innate and Adaptive Immunity
The highly variable nature of the TCR confers on the conventional T‐cell population the ability to respond to an immense array of different antigens, with individual T‐cells specific for a single antigen. Invariant natural killer T‐cells (iNKT) are a unique subset of T‐cells that display a semi‐variant TCR that equips individual iNKT cells with the ability to detect a broad array of microbial lipid antigens, presented on CD1d antigen‐presenting molecules on antigen‐presenting cells (APCs). Although conventional T‐cells are activated by APCs that have first been activated by microbial antigen (in a process that takes some time), iNKTs can respond directly to PAMPs, secreting cytokines and presenting co‐stimulatory molecules in a manner more reminiscent of innate immune cell PRR activation than T‐cell stimulation.
Figure 4.15 Natural killer T‐cells. (a) Schematic representation of type I and type II natural killer T (NKT) cells. These two subsets use different variable (V) region gene segments in the α and β chains of their T‐cell receptors (TCRs), and they recognize different CD1d‐ restricted antigens. (b) The αβTCR is composed of two chains, with the V domains containing the complementarity determining region (CDR) loops. The CDR3 loops are encoded by multiple gene segments and also contain nontemplated (N) regions, which add further diversity to the TCR repertoire. The color coding is the same as that used for the type I NKT TCR in (a). APC, antigen‐presenting cell; C, constant; D, diversity; J, joining. (Reproduced with permis sion from the authors Rossjohn et al., (2012) Nature Reviews Immunology 12, 845–857 © Nature Publishing Group.)
Although conventional CD4+ T‐cells provide help to B‐ cells as part of an adaptive immune response, iNKTs are unique in that they can provide help to B‐cells in an innate and adaptive manner, with differing outcomes. iNKTs that are activated by antigen presented on B‐cell C1d can directly license B‐cell activation in a cognate, innate‐like manner, through co‐stimulation with CD40L and the production of various cytokines, such as IFNγ and IL‐21. This leads to a restricted form of B‐ cell activation, with plasmablast expansion, early germinal center development, modest affinity maturation, and primary class‐switched antibody production, but lacking the development of plasma cells and B‐cell memory responses. Alternatively, iNKTs that have been activated by DCs presenting antigen can drive full B‐cell activation in a noncognate, or adaptive fashion, by enlisting the help of CD4+ T‐cells to license B‐cells, driving the generation of mature germinal centers, robust affinity maturation, the development of antibody‐producing plasma cells, and a B‐cell memory response.