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The Journal of Immunology, 2004, 172: 3119-3131.
Copyright © 2004 by The American Association of Immunologists

Coordinate Expression of Cytokines and Chemokines by NK Cells during Murine Cytomegalovirus Infection1

Brigitte G. Dorner2,*, Hamish R.C. Smith*, Anthony R. French*, Sungjin Kim*, Jennifer Poursine-Laurent*, Diana L. Beckman*, Jeanette T. Pingel*, Richard A. Kroczek{dagger} and Wayne M. Yokoyama3,*

* Howard Hughes Medical Institute and Division of Rheumatology, Department of Medicine, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, MO 63110; and {dagger} Molecular Immunology, Robert Koch-Institute, Berlin, Germany

Cytokines and chemokines activate and direct effector cells during infection. We previously identified a functional group of five cytokines and chemokines, namely, IFN-{gamma}, activation-induced T cell-derived and chemokine-related cytokine/lymphotactin, macrophage-inflammatory protein 1{alpha}, macrophage-inflammatory protein 1{beta}, and RANTES, coexpressed in individual activated NK cells, CD8+ T cells, and CD4+ Th1 cells in vitro and during in vivo infections. However, the stimuli during infection were not known. In murine CMV (MCMV) infection, the DAP12/KARAP-associated Ly49H NK cell activation receptor is crucial for resistance through recognition of MCMV-encoded m157 but NK cells also undergo in vivo nonspecific responses to uncharacterized stimuli. In this study, we show that Ly49H ligation by m157 resulted in a coordinated release of all five cytokines/chemokines from Ly49H+ NK cells. Whereas other cytokines also triggered the release of these cytokines/chemokines, stimulation was not confined to the Ly49H+ population. At the single-cell level, the production of the five mediators showed strong positive correlation with each other. Interestingly, NK cells were a major source of these five cytokines/chemokines in vitro and in vivo, whereas infected macrophages produced only limited amounts of macrophage-inflammatory protein 1{alpha}, macrophage-inflammatory protein1{beta}, and RANTES. These findings suggest that both virus-specific and nonspecific NK cells play crucial roles in activating and directing other inflammatory cells during MCMV infection.




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