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.
Highlights
Persistent viral infections are typically associated with a dysfunctional and exhausted T cell signature [1], mice infected with the clone 13 isolate of the lymphocytic choriomeningitis virus (LCMV) are able to control viral replication within 2–3 months post infection in a T cell dependent manner [2,3,4,5,6,7]
Numerous co-stimulatory pathways have been described and it has become evident that the biological relevance of each of those pathways is greatly dependent on the immunologic context [36], e.g. it has been shown that signaling through the costimulatory CD27/CD70 pathway can impair T cell responses during persistent infection while it positively regulates T cells during acute infection [37,38]
In order to do so, we chose to use the murine LCMV system as it offers the possibility to directly compare an acute viral infection that is effectively cleared within 7–10 days (LCMV Armstrong) to a protracted infection that persists for several weeks in various tissues (LCMV cl13)
Summary
Persistent viral infections are typically associated with a dysfunctional and exhausted T cell signature [1], mice infected with the clone 13 (cl13) isolate of the lymphocytic choriomeningitis virus (LCMV) are able to control viral replication within 2–3 months post infection in a T cell dependent manner [2,3,4,5,6,7]. The inhibitory molecules involved in T cell exhaustion have been analyzed in great detail [1,8,9,10,11]; yet, the signals that sustain T cell responses during persistent viral infections are not fully understood. This is a major concern, as, for example, the underlying cause for the loss of CD4 T cell responses during persistent viral infections in humans, such as chronic Hepatitis C Virus infection, is entirely unclear [12]. The profound impact of OX40 expression in this context is highlighted by the observation that, in contrast to wild type mice, OX40-deficient mice are incapable of controlling viral replication
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