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

Abstract

A defining characteristic of persistent viral infections is the loss and functional inactivation of antiviral effector T cells, which prevents viral clearance. Interleukin-10 (IL-10) suppresses cellular immune responses by modulating the function of T cells and antigen-presenting cells. In this paper, we report that IL-10 production is drastically increased in mice persistently infected with lymphocytic choriomeningitis virus. In vivo blockade of the IL-10 receptor (IL-10R) with a neutralizing antibody resulted in rapid resolution of the persistent infection. IL-10 secretion was diminished and interferon γ production by antiviral CD8+ T cells was enhanced. In persistently infected mice, CD8α+ dendritic cell (DC) numbers declined early after infection, whereas CD8α− DC numbers were not affected. CD8α− DCs supported IL-10 production and subsequent dampening of antiviral T cell responses. Therapeutic IL-10R blockade broke the cycle of IL-10–mediated immune suppression, preventing IL-10 priming by CD8α− DCs and enhancing antiviral responses and thereby resolving infection without causing immunopathology.

Peripheral virus-specific T-cell interleukin-10 responses develop early in acute hepatitis C infection and become dominant in chronic hepatitis

“…Interestingly, IL-10 blockade, similar to results reported by Alatrakchi et al (58), enhanced HCV-specific IFNγ response to HCV Core peptides in CD4-depleted as well as CD8-depleted PBMC, suggesting that IL-10 production by CD4 − and/or CD8 − cells (including non-T-cells such as monocytes, B-cells or NK cells) participate in HCVspecific immune regulation. Enhancement of HCV-specific effector T-cell response by IL-10R blockade has interesting therapeutic implications, particularly in light of virus control with restoration of effector T-cell function in murine LCMV infection demonstrated by IL-10 blockade in-vivo (59,60). However, the inverse association between HCV-specific Tr1 response and cirrhosis in our study suggests further caution in applying IL-10 blockade to HCV infection.…”

The enhancement of arbovirus transmission and disease by mosquito saliva is associated with modulation of the host immune response

“…The existence of viruses with IL-10 homologs reveals an evolutionary advantage to enhanced IL-10 levels for an invading virus (Griffiths 2002, SalekArdakani et al 2002. Studies with peripheral blood leukocytes found that early after infection with dengue virus (DENV), a flavivirus, increased IL-10 production induces lasting T cell inactivation and decreases the control of virus infection (Ejrnaes et al 2006). Consequently, the interaction of immunosuppressive IL-10-producing cells with T cells early during arbovirus infection may result in the loss of T-cell responsiveness, facilitate an enhancement of viral replication, and a impaired adaptive immune response.…”

Antigen amount dictates CD8+T‐cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell

“…Besides a role for immunoregulatory cytokines such as 15], , a role for inhibitory receptor expression (reviewed in [18]) and perhaps regulatory T cells [19] C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol.…”

“…This T-cell dysfunction, also termed CD8 + T-cell exhaustion, is well studied after infection of mice with a high dose of LCMV clone 13 or LCMV-Docile [13]. Infection of mice with a low dose of the same virus strains results in an acute resolved infection [13].Besides a role for immunoregulatory cytokines such as 15], , a role for inhibitory receptor expression (reviewed in [18]) and perhaps regulatory T cells [19] C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol.…”