Murine induced pluripotent stem cells can be derived from and differentiate into natural killer T cells

Abstract

NKT cells demonstrate antitumor activity when activated to produce Th1 cytokines by DCs loaded with α-galactosylceramide, the prototypic NKT cell-activating glycolipid antigen. However, most patients do not have sufficient numbers of NKT cells to induce an effective immune response in this context, indicating a need for a source of NKT cells that could be used to supplement the endogenous cell population. Induced pluripotent stem cells (iPSCs) hold tremendous potential for cell-replacement therapy, but whether it is possible to generate functionally competent NKT cells from iPSCs has not been rigorously assessed. In this study, we successfully derived iPSCs both from embryonic fibroblasts from mice harboring functional NKT cell-specific rearranged T cell receptor loci in the germline and from splenic NKT cells from WT adult mice. These iPSCs could be differentiated into NKT cells in vitro and secreted large amounts of the Th1 cytokine IFN-γ. Importantly, iPSC-derived NKT cells recapitulated the known adjuvant effects of natural NKT cells and suppressed tumor growth in vivo. These studies demonstrate the feasibility of expanding functionally competent NKT cells via an iPSC phase, an approach that may be adapted for NKT cell-targeted therapy in humans.

KLRG + invariant natural killer T cells are long-lived effectors

“…The strategy for the selective expansion of KLRG1 + iNKT cells could be explored in the future. Recently, we have successfully generated induced pluripotent stem cell (iPS)-reprogrammed iNKT cells that showed potential antitumor activity (27). Therefore, establishing a strategy for the effective generation of KLRG1 + iNKT cells by selectively expanding iNKT cells or by using the iPS-reprogrammed iNKT approach ultimately would allow us to engage in novel therapeutic interventions against human infections and cancer.…”

Generation of induced pluripotent stem cell-derived mice by reprogramming of a mature NKT cell

“…In brief, the NKT-iPSC line, designated iPSC-58 3E7, was established by reprogramming of mature splenic NKT cells from B6 mice with the Yamanaka factors (9) as previously described (7). The NKT-iPSCs were injected into BALB/c blastocysts to produce chimeric mice.…”

Invariant natural killer T cells in hematopoietic stem cell transplantation: killer choice for natural suppression

“…34 Finally, generation of induced pluripotent stem cells (iPSCs) from mature iNKTs can activate and expand Ag-specific CD8 + T cell responses to provide protection against leukemia in mice. 35 Data on the antitumor functions of human iNKTs are more indirect. Patients with various types of cancer often exhibit reduced numbers of peripheral blood iNKTs and these cells are often impaired in their functions.…”