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Invariant natural killer T (iNKT) cells are a unique T cell subset that exhibits characteristics of both innate immune cells and T cells. They express Vα14-Jα18 ( Trav11 - Traj18 ) as an invariant chain of the T cell receptor (TCR) and are restricted to the MHC class I-like monomorphic antigen presenting molecule CD1d. iNKT cells are known as immune regulators that bridge the innate and acquired immune systems by rapid and massive production of a wide range of cytokines, which could enable them to participate in immune responses during various disease states. Thus, Traj18 -deficient mice, Cd1d -deficient mice, or iNKT cell-overexpressing mice such as iNKT TCRα transgenic mice and iNKT cell cloned mice which contain a Vα14-Jα18 rearrangement in the TCRα locus are useful experimental models for the analysis of iNKT cells in vivo and in vitro . In this review, we describe the pros and cons of the various available genetically manipulated mice and summarize the insights gained from their study, including the possible roles of iNKT cells in obesity and diabetes.

iNKT cells play important roles in immune regulation by bridging the innate and acquired immune systems. The functions of iNKT cells have been investigated in mice lacking the Traj18 gene segment that were generated by traditional embryonic stem cell technology, but these animals contain a biased T cell receptor (TCR) repertoire that might affect immune responses. To circumvent this confounding factor, we have generated a new strain of iNKT cell-deficient mice by deleting the Traj18 locus using CRISPR/Cas9 technology, and these animals contain an unbiased TCR repertoire. We employed these mice to investigate the contribution of iNKT cells to metabolic disease and found a pathogenic role of these cells in obesity-associated insulin-resistance. The new Traj18-deficient mouse strain will assist in studies of iNKT cell biology.