Transcriptional regulation in the development of CD8ab+ iNKT cells in a humanized mouse model

Abstract

Abstract Invariant NKT (iNKT) cells are innate-like T cells showing potent anti-tumor function in conventional mouse models. In sharp contrast, iNKT cell ligands have had limited efficacy in human anti-tumor clinics, mostly due to the profound differences in the properties and compositions of iNKT cells between human and mice, in particular, the presence of CD8+ iNKT cells only in humans. To build more relevant in vivo models for studying human iNKT cells, we first developed a CD1d-humanized mouse model (hCD1d-KI) with human CD1d knocked in (Proc. Natl. Acad. Aci. USA 110: 2963–8, 2013). To further humanize the mouse model, we introduced human invariant TCRa chain (Va24Ja18) into the hCD1d-KI mice. Interestingly, we observed a substantial subset of iNKT cells expressing CD8ab in the new humanized mouse model (J. Immunol. 195:1459–69, 2015). The CD8ab+ iNKT cells show a strong Th1-biased cytokine response and potent cytotoxicity upon activation. The low binding of iNKT TCRs to human CD1d/lipid complex and high prevalence of Vb7 TCRb among these CD8+ iNKT cells strongly suggested a novel low avidity-based developmental program for the ontogeny of these iNKT cells which includes the suppression of the transcriptional factor, Th-POK. This suppression of Th-POK is essential for the development of CD8ab+ iNKT cells as these iNKT cells can not be detected upon forced expression of Th-POK early in T cell development. Our establishment of the new mouse model extensively humanized in CD1d/iNKT TCR system will greatly facilitate the investigation of in vivo functional properties of human iNKT cells as well as future design and optimization of iNKT cell ligands for diverse immunotherapies.