title: Interferon-γ mediates chemokine-dependent recruitment of natural killer cells during viral infection.
abstract: Natural killer (NK) cells provide in vivo control of orthopoxvirus infections in association with their expansion in the draining lymph node (LN), where they are normally very rare. The mechanism of this expansion is unclear. Herein, we determined that NK-cell depletion results in enhanced infection following footpad inoculation of cowpox virus, a natural pathogen of rodents. Following cowpox virus infection in normal mice, NK cells were greatly expanded in the draining LN, were not replicating, and displayed markers similar to splenic NK cells, suggesting specific recruitment of splenic NK cells rather than in situ proliferation. Moreover, NK-cell expansion was abrogated by prior injection of clodronate-loaded liposomes, indicating a role for subcapsular sinus macrophages. Furthermore, recruitment of transferred splenic NK cells to the draining LN was pertussis toxin-sensitive, suggesting involvement of chemokine receptors. Comprehensive analysis of chemokine mRNA expression in the draining LN following infection suggested the selective involvement of CCR2, CCR5, and/or CXCR3. Mice deficient for CCR2 or CCR5 had normal NK-cell recruitment, whereas CXCR3-deficient mice displayed a major defect, which was NK cell-intrinsic. Interestingly, both induction of transcripts for CXCR3 ligands (Cxcl9 and Cxcl10) and NK-cell recruitment required IFN-γ. These data indicate that NK-cell recruitment is mediated by subcapsular sinus macrophages, IFN-γ, and CXCR3 during orthopoxvirus infection.
authors.affiliation: Immunology Graduate Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Pak-Wittel
authors.forename: Liping
authors.initials: L
authors.lastname: Yang
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Sojka
authors.forename: Joshua G
authors.initials: JG
authors.lastname: Rivenbark
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Yokoyama
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018925:Chemokines / Q000276:immunology*; D002522:Chlorocebus aethiops; D015608:Cowpox virus / Q000276:immunology*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D007113:Immunity, Innate / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011213:Poxviridae Infections / Q000276:immunology*; D054390:Receptors, CCR2 / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D014709:Vero Cells
chemical_list: D018925:Chemokines; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D007371:Interferon-gamma