NKT cells are characterized by their expression of an NKT-cell-specific invariant antigen-receptor a chain encoded by V alpha 14J alpha 18 gene segments. These NKT cells bridge the innate and acquired immune systems to mediate effective and augmented responses; however, the limited number of NKT cells in vivo hampers their analysis. Here, two lines of induced pluripotent stem cell-derived mice (NKT-iPSC-derived mice) were generated by reprogramming of mature NKT cells, where one harbors both rearranged V alpha 14J alpha 18 and V beta 7 genes and the other carries rearranged V alpha 14J alpha 18 on both alleles but germline V beta loci. The analysis of NKT-iPSC-derived mice showed a significant increase in NKT cell numbers with relatively normal frequencies of functional subsets, but significantly enhanced in some cases, and acquired functional NKT cell maturation in peripheral lymphoid organs. NKT-iPSC-derived mice also showed normal development of other immune cells except for the absence of gamma delta T cells and disturbed development of conventional CD4 alpha beta T cells. These results suggest that the NKT-iPSC-derived mice are a better model for NKT cell development and function study rather than transgenic mouse models reported previously and also that the presence of a pre-rearranged V alpha 14J alpha 18 in the natural chromosomal context favors the developmental fate of NKT cells.
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