Role of CC chemokine receptor 4 in natural killer cell activation during acute cigarette smoke exposure

Am J Pathol. 2014 Feb;184(2):454-63. doi: 10.1016/j.ajpath.2013.10.017. Epub 2013 Dec 9.


Cigarette smoke (CS)-induced lung injury involves innate immune responses. The activation of innate effector cells is thought to require cross talk with dendritic cells (DCs) and macrophages, but the mediators of interaction are unknown. One candidate, CC chemokine receptor 4 (CCR4), is expressed by innate and adaptive effector cells, and its ligands are produced by DCs and macrophages. Using flow cytometry and confocal microscopy, we defined innate responses of lung myeloid DCs, macrophages, and conventional natural killer (NK) cells in mice exposed to CS over 4 days and examined the contribution of CCR4 using CCR4 knockout (CCR4(-/-)) mice. CS affected populations differently, causing an increase in F4/80(+) macrophages, a reduction in parenchymal CD11c(+)CD11b(+)CD103(-) DCs, but no effect on mucosal CD11c(+)CD11b(-)CD103(+) DCs. CS also induced a population of primed/activated CD69(+) NK cells and bronchoepithelial expression of the stress-related NKG2D receptor-activating protein, retinoic acid early transcript 1. CS-exposed CCR4(-/-) mice were similar to controls regarding effects on DCs and macrophages but displayed substantially impaired NK priming/activation and reduced expression of transcripts for interferon gamma, CXCL10, and retinoic acid early transcript 1. Quantitative confocal microscopy revealed that lungs of CS-exposed CCR4(-/-) mice had significantly reduced contacts of NK cells with CD11c(+) cells. These findings demonstrate that acute CS exposure elicits NK cell responses and suggest that CCR4 promotes NK cell priming/activation by mediating contacts with sentinel cells in the lung.

Publication types

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

MeSH terms

  • Animals
  • CD11c Antigen / metabolism
  • Cell Communication / immunology
  • Dendritic Cells / metabolism
  • Dendritic Cells / pathology
  • Female
  • Gene Knockout Techniques
  • Histocompatibility Antigens Class II / metabolism
  • Immunity, Innate
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / pathology
  • Ligands
  • Lung / pathology
  • Lymphocyte Activation / immunology*
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, CCR4 / deficiency
  • Receptors, CCR4 / metabolism*
  • Smoking / adverse effects*
  • Time Factors


  • CD11c Antigen
  • Ccr4 protein, mouse
  • Histocompatibility Antigens Class II
  • Ligands
  • Membrane Proteins
  • RNA, Messenger
  • Receptors, CCR4