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Proc Natl Acad Sci U S A. 2015 Feb 3;112(5):1523-8. doi: 10.1073/pnas.1424877112. Epub 2015 Jan 20.

Genetic engineering of hematopoietic stem cells to generate invariant natural killer T cells.

Author information

1
Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Department of Microbiology, Immunology and Molecular Genetics, and.
2
Department of Microbiology, Immunology and Molecular Genetics, and.
3
Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research.
4
Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Department of Microbiology, Immunology and Molecular Genetics, and Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095 liliyang@ucla.edu owenwitte@mednet.ucla.edu.
5
Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Department of Microbiology, Immunology and Molecular Genetics, and liliyang@ucla.edu owenwitte@mednet.ucla.edu.

Abstract

Invariant natural killer T (iNKT) cells comprise a small population of αβ 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.

KEYWORDS:

HSCs; genetic engineering; hematopoietic stem cells; iNKT cells; invariant natural killer T cells

PMID:
25605948
PMCID:
PMC4321292
DOI:
10.1073/pnas.1424877112
[Indexed for MEDLINE]
Free PMC Article

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