Abstract
Upon infection with persistence-prone virus, type I interferon (IFN-I) mediates antiviral activity and also upregulates the expression of programmed death ligand 1 (PD-L1), and this upregulation can lead to CD8+ T-cell exhaustion. How these very diverse functions are regulated remains unknown. This study, using the lymphocytic choriomeningitis virus, showed that a subset of CD169+ macrophages in murine spleen and lymph nodes produced high amounts of IFN-I upon infection. Absence of CD169+ macrophages led to insufficient production of IFN-I, lower antiviral activity and persistence of virus. Lack of CD169+ macrophages also limited the IFN-I-dependent expression of PD-L1. Enhanced viral replication in the absence of PD-L1 led to persistence of virus and prevented CD8+ T-cell exhaustion. As a consequence, mice exhibited severe immunopathology and died quickly after infection. Therefore, CD169+ macrophages are important contributors to the IFN-I response and thereby influence antiviral activity, CD8+ T-cell exhaustion and immunopathology.
Highlights
Upon infection with persistence-prone virus, type I interferon (IFN-I) mediates antiviral activity and upregulates the expression of programmed death ligand 1 (PD-L1), and this upregulation can lead to CD8+ T-cell exhaustion
CD169 was mostly upregulated in the bone marrow, on different cell populations in the spleen and on F4/80+ and Ly6C+ cells in the liver, whereas we did not detect an upregulation of CD169 in the lymph nodes (LNs) (Supplementary Figure S2 and Figure 1b)
We showed that infecting wild type (WT) mice with low dose of lymphocytic choriomeningitis virus (LCMV)-WE (⩽200 plaque-forming units (PFU)) leads to viral replication only in the spleen but not in the liver
Summary
Upon infection with persistence-prone virus, type I interferon (IFN-I) mediates antiviral activity and upregulates the expression of programmed death ligand 1 (PD-L1), and this upregulation can lead to CD8+ T-cell exhaustion. The absence of the interferon-α/β receptor (IFNAR) promotes viral replication and can result in persistence of virus.[4,5,6] On the other hand, sustained IFN-I signaling induces immunosuppressive mechanisms, including the production of interleukin-10 (IL-10) and the expression of programmed cell death ligand 1 (PD-L1).[7,8,9] IL-10 and PD-L1 are important inhibitors of CD8+ T cells and thereby limit the function of virus-specific CD8+ T cells.
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