Development of CD8αβ+ iNKT cells in a humanized mouse model (APP3P.112)

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, including the presence of CD8+ iNKT cells only in humans. To build more relevant in vivo models for studying human iNKT cells, we recently developed the first 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 TCRα chain (Vα24Jα18) into the hCD1d-KI mice. Interestingly, we observed a substantial subset of iNKT cells expressing CD8αβ. The presence of these CD8αβ+ cells in the thymus suggested that they are developed in the thymus. Functionally these 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 Vβ7 TCRβ 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 Th-POK and up-regulation of Eomes transcriptional factors. Our establishment of a near fully-humanized mouse model in CD1d/iNKT TCR system will greatly facilitate the future design and optimization of iNKT cell-based immunotherapies.