In this study we showed that the WT (C57BL/6) mice previously infected with VSV (highly cytopathic virus) induces IFN-α anergy after Poly (I.C) rechallenge. We demonstrated that IFN-α anergy was associated with induction of apoptotic cells as infection with VSV enhanced active caspase-3 detection and this correlated with reduced cell viability and increased phosphatidylserine (PS) expression. In line, pretreatment of BDMCs derived from WT mice with dead cells significantly blunted IFN-α induction after VSV challenge. We speculated that Mertk as a sensor of PS on apoptotic cells may be involved in innate anergy after acute viral infection. First, we showed that macrophages and DCs strongly express TAM receptor Mertk. Next, we demonstrated that Mertk deficiency strongly enhanced IFN-1, TNF-α and IL-6 production but lack of Mertk abrogates IFN-α anergy after VSV infection. We proposed that dead cells may activate Mertk signals and this activation can induce other inhibitory signals that dampen antiviral responses. We showed that induction of Mertk signal after VSV challenge results in upregulation of SOCS1, SOCS3, IL-10 and TGF-β. In line, pretreatment of BMDCs derived from WT mice with dead cells strongly induced IL10 expression, which was significantly prevented in Mertk deficient mice. In fact, lack of Mertk limited the expression of these inhibitory proteins and promotes innate antiviral response. We further determined the overall influence of Mertk on antiviral response. We found that genetic deletion or pharmacological inhibition of Mertk reduces VSV titers in the spleen, liver, kidney, lungs, and lymph nodes. Similar to IRF-3 and IRF-7 upregulation, ISG15, OAS1, and MX1 were highly induced in Mertk deficient mice and resulted in better survival of infection. Additionally, deficiency of Mertk enhances IFN-γ production by CD4+ and CD8+ T cells. Though the neutralizing capacities were similar, we suggested that the enhanced IFN-1 production by Mertk–/– mice was sufficient to allow the host to survive the infection. Meanwhile LCMV is completely non cytopathic virus and causes chronic infections, it has been found to result in dramatic CD8 T‐cell expansion and acquisition of effector function and cytotoxic T cells kill their targets by programming them to undergo apoptosis. Based on this finding, we proposed that the apoptotic CD8T cells or CD8 T cell killed target cells might induce inhibitory signals via Mertk that limits CD8T cell function. Indeed, lack of T cells in TCR-beta deficient mice prevented the induction of apoptotic cells as detected by active caspase-3 suggesting that the CD8Tcells T cell response against the virus not the virus itself are inducing the dead cells. The induction of active caspase 3 correlated with upregulation of Mertk in WT mice. WT mice showed reduced Virus specific CD8Tcells and CD8+Tcell expansion, and increased expression of IL10, which is a master regulator of immune response. Similarly, expression of PD1 on CD8+ T cells and virus specific CD8+ T cells was strongly upregulated in WT mice. In fact, lack of Mertk limited PD1 expression and augmented CD8+ T cell function suggesting that Mertk is a promoter of T cells exhaustion. Evaluating immune-pathological consequences of this highly activated CD8+Tcells status, we showed that Mertk–/– mice transiently enhanced liver transaminases. Exploiting dexamethasone as a known inducer of rat thymic apoptosis to enhance Mertk expression in vivo, we proposed that upregulation of Mertk by dexamethasone can limit antiviral response. We showed that pretreatment of WT mice with dexamethasone substantially increased Mertk expression and this was associated with disseminated VSV replication in spleen, liver, kidney, lungs, and lymph nodes. In line, we observed significant increase in SOCS1 and SOCS3 expression and suppressed IFN-1production in dexamethasone-pretreated WT mice. Similarly, after infection with chronic virus, virus specific CD8Tcells and CD8Tcell proliferation was greatly abrogated in dexamethasone pre-treated WT mice. Lack of Mertk abolished the immunosuppressive effect of dexamethasone. In conclusion, dead cells induce tolerogenic state via Mertk. The induction of SOCS1, SOCS3, IL-10, and TGF-β after the activation of Mertk signals extinguishes antiviral mechanisms and results in innate anergy after acute VSV challenge. Mertk regulates adaptive immune response via IL10 and promotes exhausted CD8+Tcell phenotype during chronic LCMV infection.