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Abstract
Tumor progression locus 2 (Tpl2), also designated Cot or MAP3K8, is a serine-threonine kinase with critical functions in regulating innate and adaptive immune responses. Although Tpl2 is known to be important in the regulation of major immunomodulatory cytokines, including antiviral Type I and Type II interferons (IFNs), and in host protection against various bacterial and parasitic infections, remarkably little is known about how Tpl2 might contribute to host defense against viruses. In this study, Tpl2 activation during pathogen sensing as well as Tpl2 regulation of virus replication and antiviral immune responses were investigated. Even though Tpl2 is an integral component of pathogen sensing pathways, differential activation of Tpl2-ERK signaling was observed in response to model microbial ligands. While a subset of toll-like receptors (TLRs), including virus-sensing TLR7, directly activate the Tpl2-extracellular signal-regulated kinase (ERK) pathway, TLR3 and TLR9 activate ERK indirectly via autocrine signaling by reactive oxygen species (ROS), which is generated in a Tpl2-dependent manner. Consistent with its activation during pathogen sensing, Tpl2 regulates Type I and Type III IFN production upon stimulation of TLR and RIG-I like helicases involved in virus sensing. However, only Type III IFN induction required Tpl2 during influenza virus infection in vitro and in vivo. In addition to the regulation of IFN production, Tpl2 is also important in transducing Type I IFN signals that promote the expression of antiviral genes to limit virus replication. Moreover, Tpl2-/- mice showed impaired expansion of virus-specific CD8+ T cells that facilitate viral clearance. Secretion of antigen-specific IFN was also decreased in Tpl2-/- cells. Experiments using in vitro cultured CD8+ T cells revealed a cell-intrinsic role for Tpl2 in promoting effector CD8+ T cell responses. Consistent with its critical role in facilitating both innate and adaptive antiviral responses, Tpl2 was necessary for controlling virus replication and restricting morbidity and mortality associated with influenza virus infection. Collectively, these studies establish Tpl2 as a host factor that promotes virus sensing and integrates antiviral innate and adaptive immune responses.