Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 5, Pages 1523-1528Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1424877112
Keywords
genetic engineering; hematopoietic stem cells; HSCs; invariant natural killer T cells; iNKT cells
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Funding
- UCLA BSCRC Innovation Award
- UCLA SPORE in Prostate Cancer Career Development Award (NIH) [P50 CA092131]
- Concern Foundation Stem Cell Research Award
- California Institute for Regenerative Medicine (CIRM) Basic Biology V Exploratory Concepts Award [RB5-07089]
- National Institutes of Health (NIH) Director's New Innovator Award [DP2 CA196335]
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research
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Invariant natural killer T (iNKT) cells comprise a small population of alpha 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 (similar to 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.
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