Cytomegalovirus exploits IL-10-mediated immune regulation in the salivary glands.
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.
Humphreys
Ian R
IR
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
de Trez
Carl
C
Kinkade
April
A
Benedict
Chris A
CA
Croft
Michael
M
Ware
Carl F
CF
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology*; D017931:DNA Primers; D005260:Female; D005434:Flow Cytometry; D006566:Herpesviridae Infections / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus / Q000276:immunology / Q000502:physiology*; D053701:Receptors, Interleukin-10 / Q000037:antagonists & inhibitors; D053262:Receptors, OX40 / Q000819:agonists; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012469:Salivary Glands / Q000276:immunology* / Q000821:virology; D014779:Virus Replication / Q000502:physiology*
D000906:Antibodies; D017931:DNA Primers; D053701:Receptors, Interleukin-10; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; D016753:Interleukin-10; D007371:Interferon-gamma