The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20062424
The Journal of Experimental Medicine, Vol. 204, No. 5, 1217-1225
The Rockefeller University Press, 0022-1007 $30.00
© Humphreys et al.
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ARTICLE

 Cytomegalovirus exploits IL-10–mediated immune regulation in the salivary glands

Ian R. Humphreys, Carl de Trez, April Kinkade, Chris A. Benedict, Michael Croft, and Carl F. Ware

Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037

CORRESPONDENCE Carl F. Ware: cware{at}liai.org OR Michael Croft: mick{at}liai.org

The salivary glands represent a major site of cytomegalovirus replication and transmission to other hosts. Despite control of viral infection by strong T cell responses in visceral organs cytomegalovirus replication continues in the salivary glands of mice, suggesting that the virus exploits the mucosal microenvironment. Here, we show that T cell immunity in the salivary glands is limited by the induction of CD4 T cells expressing the regulatory cytokine interleukin (IL)-10. Blockade of IL-10 receptor (IL-10R) with an antagonist antibody dramatically reduced viral load in the salivary glands, but not in the spleen. The mucosa-specific protection afforded by IL-10R blockade was associated with an increased accumulation of CD4 T cells expressing interferon {gamma}, suggesting that IL-10R signaling limits effector T cell differentiation. Consistent with this, an agonist antibody targeting the tumor necrosis factor receptor superfamily member OX40 (TNFRSF4) enhanced effector T cell differentiation and increased the number of interferon {gamma}–producing T cells, thus limiting virus replication in the salivary glands. Collectively, the results indicate that modulating effector T cell differentiation can counteract pathogen exploitation of the mucosa, thus limiting persistent virus replication and transmission.

Abbreviations used: HCMV, human CMV; MCMV, mouse CMV; T reg, T regulatory.


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