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Cell. 2014 Sep 25;159(1):94-107. doi: 10.1016/j.cell.2014.08.026.

The RAG recombinase dictates functional heterogeneity and cellular fitness in natural killer cells.

Author information

1
Immunology Program and Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Department of Immunobiology and the Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
3
Immunology Program and Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: sunj@mskcc.org.

Abstract

The emergence of recombination-activating genes (RAGs) in jawed vertebrates endowed adaptive immune cells with the ability to assemble a diverse set of antigen receptor genes. In contrast, innate lymphocytes, such as natural killer (NK) cells, are not believed to require RAGs. Here, we report that NK cells unable to express RAGs or RAG endonuclease activity during ontogeny exhibit a cell-intrinsic hyperresponsiveness but a diminished capacity to survive following virus-driven proliferation, a reduced expression of DNA damage response mediators, and defects in the repair of DNA breaks. Evidence for this novel function of RAG has also been observed in T cells and innate lymphoid cells (ILCs), revealing an unexpected role for RAG proteins beyond V(D)J recombination. We propose that DNA cleavage events mediated by RAG endow developing adaptive and innate lymphocytes with a cellular "fitness" that safeguards their persistence later in life during episodes of rapid proliferation or cellular stress.

PMID:
25259923
PMCID:
PMC4371485
DOI:
10.1016/j.cell.2014.08.026
[Indexed for MEDLINE]
Free PMC Article
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