Development of humanized mouse models for in vivo studies of human iNKT cells — ASN Events
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  3. Development of humanized mouse models for in vivo studies of human iNKT cells

Development of humanized mouse models for in vivo studies of human iNKT cells (#103)

Xiangshu Wen 1 , Seil Kim 1 , Michelle Li 1 , Ping Rao 1 , Omid Akbari 1 , Remy Bosselut 2 , Paolo Dellabona 3 , Giulia Casorati 3 , Mark Exley 4 , Weiming Yuan 1 5
  1. University of Southern California, Los Angeles, CA, United States
  2. Center for Cancer Research National Cancer Institute, Bethesda, MA, USA
  3. Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy
  4. Agenus, Inc and Harvard Medical School, Boston, MA, USA
  5. Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, 90033

Invariant NKT (iNKT) cells are innate-like T cells, which demonstrate potent anti-tumor function in mouse models. In sharp contrast, iNKT cell ligands have shown limited efficacy in human anti-tumor clinics, mostly due to the significant differences in CD1d lipid presentation properties and profound disparity in the composition and abundance of iNKT cells between human and mice. To build more relevant in vivo models for studying human iNKT cells, we have 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 human-like iNKT cell abundance and co-receptor expression pattern in the humanized mouse models. In particular, we detected a substantial subset of iNKT cells expressing CD8ab (J. Immunol. 195:1459-69, 2015). The CD8ab+ iNKT cells show a strong Th1-biased cytokine response and potent cytotoxicity upon activation. The lower binding of iNKT TCRs to human CD1d/lipid complex than that of mouse counterparts as well as higher prevalence of Vb7 TCRb in these CD8+ iNKT cells suggested a low avidity-based developmental program for these iNKT cells which includes the suppression of the transcriptional factor, Th-POK. Using a Th-POK-transgenic mouse, we demonstrated that the suppression of Th-POK is essential for the development of CD8ab+ iNKT cells. Our establishment of the new humanized mouse models will facilitate the investigation of in vivo functional properties of human iNKT cells and identification of optimal glycolipid ligands for iNKT cell-based immunotherapies.