OX40 Facilitates Control of a Persistent Virus Infection

Abstract

During acute viral infections, clearance of the pathogen is followed by the contraction of the anti-viral T cell compartment. In contrast, T cell responses need to be maintained over a longer period of time during chronic viral infections in order to control viral replication and to avoid viral spreading. Much is known about inhibitory signals such as through PD-1 that limit T cell activity during chronic viral infection, but little is known about the stimulatory signals that allow maintenance of anti-viral T cells. Here, we show that the co-stimulatory molecule OX40 (CD134) is critically required in the context of persistent LCMV clone 13 infection. Anti-viral T cells express high levels of OX40 in the presence of their cognate antigen and T cells lacking the OX40 receptor fail to accumulate sufficiently. Moreover, the emergence of T cell dependent germinal center responses and LCMV-specific antibodies are severely impaired. Consequently, OX40-deficient mice fail to control LCMV clone 13 infection over time, highlighting the importance of this signaling pathway during persistent viral infection.

Author Summary

A robust T cell response is the hallmark of an effective immune response to a variety of invading viruses. In many acute infections, the clearance of the viral pathogen is associated with a short and vigorous T cell response followed by development of pathogen-specific immune memory. However, some viruses can establish persistent infection in their respective host, during which an ongoing T cell response is required in order to prevent overwhelming viral replication. Little is known about the factors that sustain the T cell response in the persistent phase of a viral infection. In this report, we demonstrate that ligation of the OX40 molecule, which is expressed on T cells targeting the virus, is critically required in order to sustain the anti-viral immune response. We show that virus-specific, OX40-deficient T cells fail to accumulate sufficiently and consequently, mice lacking the OX40 receptor are incapable of controlling viral replication. Collectively our data establish OX40 as a crucial signaling molecule during a persistent viral infection.