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Title: OX40 Facilitates Control of a Persistent Virus Infection}
Article:
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.
Introduction:
Although 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]–[7]. The inhibitory molecules involved in T cell exhaustion have been analyzed in great detail[1],[8]–[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]. While recent studies demonstrated important roles for the Interleukins 21 and 6 in this context[2]–[4],[13], little is known about the role of co-stimulatory signals. OX40( CD134) is a co-stimulatory molecule that has been shown to be important for T cell survival and function as well as establishment of T cell memory, although the degree to which OX40 influences immune responses is greatly context dependent[14]–[16]. While OX40 plays a role in driving T cell responses to several viruses[17]–[19], interestingly, it seems to be largely dispensable in the setting of acute LCMV infection. Although the LCMV-specific CD4 T cell responses in OX40-deficient mice are impaired, CD8 T cell responses, antibody titers and pathogen control are largely unaltered following acute LCMV infection[20]. However, the importance of OX40 during chronic viral infections remains unclear. Since OX40 signaling has the ability to promote long-term survival of T cells, we hypothesized that its biological relevance might be more prominent in the context of viral persistence. Indeed, in stark contrast to what has been observed during acute LCMV infection, we show that OX40 shapes both the CD4 and CD8 T cell response during persistent LCMV cl13 infection including T cell dependent antibody responses. 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.
Discussion:
Co-stimulation of T cells is a central component of adaptive immunity. 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 co-stimulatory CD27/CD70 pathway can impair T cell responses during persistent infection while it positively regulates T cells during acute infection[37],[38]. Thus, it is of great interest to define those co-stimulatory pathways that dominantly influence adaptive immunity in a given disease model. 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). Our findings demonstrate that OX40-deficiency profoundly impacted the anti-viral immune response during persistent LCMV cl13 infection. Although the role of OX40 has never been studied in a persistent viral infection with ongoing viral replication, much is known about the mechanisms by which OX40 can influence T cell responses. It has been demonstrated that OX40 promotes T cell survival, division and function in various immune models, including cancer models[39]–[41], viral[17],[18] and bacterial[31] infection as well as autoimmunity[42],[43]. Interestingly, during persistent infection, the role of OX40 seems to be largely restricted to promoting T cell survival, as we have not observed differences in T cell proliferation or cytokine production in the absence of OX40. In previous publications it has been shown that the ability of OX40 to promote T cell survival is based on its capacity to directly recruit and activate various intracellular signaling pathways, such as PI3K and Akt/PKB or NF-κB[33]–[35],[44]. These pathways control the expression of anti-apoptotic members of the Bcl-2 family and T cells that lack OX40 express reduced levels of Bcl-2, Bcl-xL, and Bfl-1[14],[32]. Restoration of NF-κB activity or Akt activity through retroviral introduction of active IκB kinase or active Akt rescues survival and Bcl-2/Bcl-xL expression in OX40 deficient T cells[33]–[35]. We show here that OX40-deficient cells fail to accumulate, are more prone to apoptosis and display reduced levels of Bcl-2 and Bcl-xL, strongly suggesting that the OX40 induced signaling axis that controls the expression of anti-apoptotic molecules is functional in the context of persistent viral infection. Although OX40 has primarily been associated with CD4 T cell function, it became evident in recent years that it can also strongly influence CD8 T cells[15],[17]. We observed much higher levels of OX40 expression on the anti-viral CD4 T cells compared to CD8 T cells, suggesting that OX40 might predominantly shape the CD4 response in this context. Consequently, the impaired CD8 T cell and B cell responses in the OX40-deficient mice could have been a result of insufficient CD4 T cell help as CD4 T cells are key players in providing help to both CD8 T cells and B cells. However, our adoptive cell-transfer model clearly demonstrates a crucial requirement of OX40 on both CD4 and CD8 T cells in order to accumulate sufficiently, implying direct OX40 signaling to CD8 T cells is likely important. Another observation of our study that is noteworthy is how OX40 deficiency impacts the antiviral immune response already at early stages post infection, however, loss of viral control in those mice occurs in a delayed fashion. The notion that changes in the immune response can precede differences in viral titers in the LCMV cl13 system has been described before[4],[5],[45]. Indeed, even though anti-viral T cell numbers and LCMV-specific antibody-titers were markedly different as soon as day 10 and 20 post infection, this had no immediate impact on viral control and viral titers initially declined in both WT and OX40-deficient mice. Moreover, OX40-deficient mice had a clinical benefit from the weak immune response and displayed reduced signs of immunopathology. Thus, it seems that the amount of T cells that accumulates in WT mice in an OX40-dependent manner during early stages exceeds the number that is required for initial virus control. And while this over-abundance of pro-inflammatory effector T cells mediates immunopathology, it does enable stronger T cell pressure on viral replication over time, which eventually facilitates virus control. While OX40 has previously been shown to positively regulate antigen-specific immune responses, the degree to which OX40 influences adaptive immunity and, importantly, facilitates virus control in the context of persistent infection is remarkable. Indeed, the strong impact of OX40 on the cellular and humoral immunity in the persistent LCMV-system is in contrast to previous findings in the acute LCMV system, where the absence of OX40 primarily affected the magnitude of the CD4 T cell response but did not have an impact on the antiviral CD8 T cell response, antibody titers and virus control[20]. Since our data suggest that OX40 expression is associated with antigen recognition, the rapid elimination of antigen in the acute infection model might be responsible for the loss of OX40 expression and thus, the reduction of biological relevance of OX40 signaling during acute infection. Those observations demonstrate different OX40 requirements for T cell accumulation during acute vs. persistent LCMV infection and, in addition, support our previous finding that OX40 usage may be dictated by the virulence of an invading pathogen[16]. While CD8 T cell responses have long been known to be critical for control of persistent LCMV-infection, the relevance of antibody responses in this context may have been underappreciated. Importantly, Pinschewer and colleagues showed that mice that were unable to produce LCMV-specific antibodies failed to control infection[46] and more recently, striking defects in control of LCMV cl13 were observed when antibody responses were reduced due to defective follicular T helper cell responses[5],[13]. These studies have established a strong role for T cell dependent humoral immunity in the control of persistent viruses and one study has demonstrated an important role of IL-6 in this context[13]. Our work, which we report in this manuscript, extends those observations and clearly establishes a critical role for OX40 in sustaining follicular T helper cell responses in the context of persistent viral infection. Importantly, these findings could open new paths in the understanding of T cell failure during persistent viral infections in humans, i. e. chronic HCV infection. Particularly HCV-specific CD4 responses are very weak in persistently infected individuals[47],[48] and recently, it has been shown that CD4 T cell priming and accumulation occurs in the acute phase of HCV infection. However, in many cases, those CD4 responses rapidly disappear, severely increasing the risk of developing persistent viremia[12]. The rapid loss of CD4 responses in OX40 deficient mice is somewhat reminiscent of this observation, suggesting that OX40 might be an interesting molecule to study in those patients. The findings regarding the role of OX40 in the antibody response to a persisting virus might also be relevant to HIV infection in humans, as there is an intense interest in broadly neutralizing antibodies and why they only develop in a small subset of HIV-infected individuals[49],[50]. Collectively, our findings establish OX40 as a key factor in sustaining the cellular and humoral immunity during viral persistence and have important implications for the study of T cell dysfunction in persistent viral infections in humans.
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 .