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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytomegalovirus Infections / immunology
  • DNA Breaks, Double-Stranded
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Lymphocytes / immunology
  • Mice, Inbred C57BL
  • Mice, SCID
  • Muromegalovirus / physiology
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • V(D)J Recombination


  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Rag2 protein, mouse
  • RAG-1 protein