期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：5
页码：1523-1528
DOI：10.1073/pnas.1424877112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThis article describes a new method for generating large numbers of invariant natural killer T (iNKT) cells in mice through genetic engineering of blood stem cells. iNKT cells are potent immune cells that regulate many human diseases, including cancer, infections, allergies, and autoimmunity. However, both the study of iNKT cell biology and the clinical application of iNKT cells have been greatly hindered by their small numbers ([~]0.01-1% in mouse and human blood). The method reported here provides a powerful new tool to study iNKT cell biology in a mouse model. It can also be applied to humans, opening a new avenue for iNKT cell-based immunotherapy that has the potential to provide patients with therapeutic levels of iNKT cells throughout life. Invariant natural killer T (iNKT) cells comprise a small population of {beta} T lymphocytes. They bridge the innate and adaptive immune systems and mediate strong and rapid responses to many diseases, including cancer, infections, allergies, and autoimmunity. However, the study of iNKT cell biology and the therapeutic applications of these cells are greatly limited by their small numbers in vivo ([~]0.01-1% in mouse and human blood). Here, we report a new method to generate large numbers of iNKT cells in mice through T-cell receptor (TCR) gene engineering of hematopoietic stem cells (HSCs). We showed that iNKT TCR-engineered HSCs could generate a clonal population of iNKT cells. These HSC-engineered iNKT cells displayed the typical iNKT cell phenotype and functionality. They followed a two-stage developmental path, first in thymus and then in the periphery, resembling that of endogenous iNKT cells. When tested in a mouse melanoma lung metastasis model, the HSC-engineered iNKT cells effectively protected mice from tumor metastasis. This method provides a powerful and high-throughput tool to investigate the in vivo development and functionality of clonal iNKT cells in mice. More importantly, this method takes advantage of the self-renewal and longevity of HSCs to generate a long-term supply of engineered iNKT cells, thus opening up a new avenue for iNKT cell-based immunotherapy.
