Resolution of a chronic viral infection after interleukin-10 receptor blockade

doi:10.1084/jem.20061462

Published online 9 October 2006. doi:10.1084/jem.20061462

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Resolution of a chronic viral infection after interleukin-10 receptor blockade

Mette Ejrnaes¹, Christophe M. Filippi¹, Marianne M. Martinic¹, Eleanor M. Ling¹, Lisa M. Togher¹, Shane Crotty², and Matthias G. von Herrath¹

¹ Immune Regulation Lab – DI3 and ² Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037

CORRESPONDENCE Matthias G. von Herrath: matthias{at}liai.org

A defining characteristic of persistent viral infections isthe loss and functional inactivation of antiviral effector Tcells, which prevents viral clearance. Interleukin-10 (IL-10)suppresses cellular immune responses by modulating the functionof T cells and antigen-presenting cells. In this paper, we reportthat IL-10 production is drastically increased in mice persistentlyinfected with lymphocytic choriomeningitis virus. In vivo blockadeof the IL-10 receptor (IL-10R) with a neutralizing antibodyresulted in rapid resolution of the persistent infection. IL-10secretion was diminished and interferon ${gamma}$ production by antiviralCD8⁺ T cells was enhanced. In persistently infected mice, CD8 ${alpha}$ ⁺dendritic cell (DC) numbers declined early after infection,whereas CD8 ${alpha}$ ^– DC numbers were not affected. CD8 ${alpha}$ ^–DCs supported IL-10 production and subsequent dampening of antiviralT cell responses. Therapeutic IL-10R blockade broke the cycleof IL-10–mediated immune suppression, preventing IL-10priming by CD8 ${alpha}$ ^– DCs and enhancing antiviral responsesand thereby resolving infection without causing immunopathology.

Abbreviations used: BFA, Brefeldin A; HCV, hepatitis C virus;LCMV, lymphocytic choriomeningitis virus; PD-1, programmed death1 receptor; TLR, Toll-like receptor.

M. Ejrnaes, C.M. Filippi, and M.M. Martinic contributed equallyto this paper.

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