Murine natural killer cell licensing and regulation by T regulatory cells in viral responses

Proc Natl Acad Sci U S A. 2013 Apr 30;110(18):7401-6. doi: 10.1073/pnas.1218767110. Epub 2013 Apr 15.


Natural killer (NK) cells show differential functionality based on their capability of binding to self-MHC consistent with licensing. Here we show in vivo confirmation of the physiologic effects of licensing with differential effects of NK subsets on anti-murine cytomegalovirus (anti-MCMV) responses after syngeneic hematopoietic stem cell transplantation (HSCT) or regulatory T-cell (Treg) depletion. After HSCT, depletion of licensed NK cells led to far greater viral loads in target organs early after infection compared with nondepleted and unlicensed depleted mice. There was a preferential expansion of licensed, C-type lectin-like activating receptor Ly49H+ NK cells with increased IFNγ production after infection in nondepleted mice post-HSCT and after Treg depletion. Adoptive transfer of licensed NK subsets into immunodeficient hosts provided significantly greater MCMV resistance compared with transfer of total NK populations or unlicensed subsets. In non-HSCT mice, only concurrent depletion of Tregs or TGF-β neutralization resulted in detection of NK licensing effects. This suggests that licensed NK cells are the initial and rapidly responding population of NK cells to MCMV infection, but are highly regulated by Tregs and TGF-β.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adoptive Transfer
  • Animals
  • Cell Proliferation
  • Female
  • Hematopoietic Stem Cell Transplantation / adverse effects
  • Herpesviridae Infections / immunology
  • Herpesviridae Infections / pathology
  • Herpesviridae Infections / prevention & control
  • Herpesviridae Infections / virology
  • Interferon-gamma / biosynthesis
  • Killer Cells, Natural / immunology*
  • Lymphocyte Depletion
  • Mice
  • Mice, Congenic
  • Mice, Inbred C57BL
  • Muromegalovirus / immunology*
  • NK Cell Lectin-Like Receptor Subfamily A / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / metabolism
  • Viral Load / immunology


  • NK Cell Lectin-Like Receptor Subfamily A
  • Transforming Growth Factor beta
  • Interferon-gamma