Interferon-γ mediates chemokine-dependent recruitment of natural killer cells during viral infection

Melissa A. Pak-Wittel, Liping Yang, Dorothy K. Sojka, Joshua G. Rivenbark, Wayne M. Yokoyama

Research output: Contribution to journalArticle

60 Scopus citations

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. Themechanism 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.

Original languageEnglish
Pages (from-to)E50-E59
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number1
DOIs
StatePublished - Jan 2 2013

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