A unique human-like CD8+ iNKT cells in a humanized mouse model (APP2P.113)

Abstract The distinct differences in CD1d/NKT lipid presentation systems in humans and mice largely account for the minimal success of Natural Killer T (NKT) cell-based anti-tumor clinical trials in humans, contrasting their strong anti-tumor effects in conventional mouse models. We aim to humanize mice at the molecular level to better model human CD1d/NKT lipid presentation in vivo. Previously, we reported a novel human CD1d knock-in (hCD1d-KI) mouse, which contain a human-like abundance of iNKT cells yet possess potent anti-tumor immunity by the iNKT cells (Proc. Natl. Acad. Aci. USA 110: 2963-8, 2013). To further humanize the CD1d/NKT lipid presentation system, we have introduced the human Vα24 TCR transgene into the KI mice. These mice have comparable numbers of iNKT cells in thymus and spleen, but significant reduced numbers in liver comparing to Vα24Tg mice. These iNKT cells predominantly express mouse Vβ8 TCR, the homolog of human Vβ11, with reduced CD4 expression. Importantly, we detected in these mice a unique population of CD8+ iNKT cells, which exist in human, but not in wild type mice. Bone marrow transfer experiments suggested that CD8+ iNKT cells are hCD1d-dependent. These CD8+ iNKT cells produce cytokines upon activation and are cytotoxic to B16 melanoma cells in vitro. The hCD1d KI-Vα24Tg mice will allow more accurate in vivo modeling of the human CD1d lipid presentation to human iNKT cells and will facilitate the preclinical assessment of iNKT cell-based therapies.