Toward realization of the promise of regenerative medicine

Abstract Somatic cell nuclear transfer allows the generation of cloned embryonic stem cells (ESC) and cloned mice from natural killer T (NKT) cells, an innate-type invariant T cell. The progeny of these cloned mice harboring a rearranged T cell receptor α loci specific for NKT cells, Vα14-Jα18, possess an increased number of NKT cells in the primary as well as in the secondary lymphoid organs. NKT cells in these mice are able to produce interferon-γ (IFN-γ) and interleukin-4 (IL-4) when stimulated with dendritic cells (DC) pulsed with an NKT cell agonist, α-galactosylceramide (α-GalCer). The directed differentiation of cloned ESC toward T cells results in quasi-exclusive generation of NKT cells. These NKT cells are functional as evidenced by the production of cytokines such as IFN-γ, IL-4, IL-10, and IL-13 in response to α-GalCer. Furthermore, they mature autonomously in vivo upon adoptive transfer, and exhibit an antigen-specific adjuvant effect, resulting in IFN-γ production from CD8+ T cells. This effect is evident when the growth of tumors is inhibited in an antigen-dependent manner upon tumor inoculation into the mouse. Unfortunately, in humans, NKT cells are rare, and there is no guarantee that the same technique will be applicable for use in the clinic. We, therefore, exploited a different type of T cells in humans. We established induced pluripotent stem cells (iPSC) from these T cells, and succeeded in directed differentiation of the iPSC into monoclonal T cells. The availability of iPSC-derived monoclonal T cells paves the way for their use in regenerative medicine. In addition, they will be useful for drug screening to target unmet medical needs such as autoimmunity, severe infection, allergy, and cancer.