Cross-presenting CD103+ dendritic cells are protected from influenza virus infection

Abstract

CD8 + cytotoxic T cells are critical for viral clearance from the lungs upon influenza virus infection. The contribution of antigen cross-presentation by DCs to the induction of anti-viral cytotoxic T cells remains controversial.Here, we used a recombinant influenza virus expressing a nonstructural 1-GFP (NS1-GFP) reporter gene to visualize the route of antigen presentation by lung DCs upon viral infection in mice. We found that lung CD103 + DCs were the only subset of cells that carried intact GFP protein to the draining LNs. Strikingly, lung migratory CD103 + DCs were not productively infected by influenza virus and thus were able to induce virus-specific CD8 + T cells through the cross-presentation of antigens from virally infected cells. We also observed that CD103 + DC resistance to infection correlates with an increased anti-viral state in these cells that is dependent on the expression of type I IFN receptor. These results show that efficient cross-priming by migratory lung DCs is coupled to the acquisition of an anti-viral status, which is dependent on the type I IFN signaling pathway. IntroductionThe identification of the mechanisms that control the initiation of anti-influenza virus CD8 + T cell responses that clear viral infections requires knowledge of the identity of the APCs and the location and time of antigen presentation by APCs to T lymphocytes. In viral infections, DCs could potentially acquire viral antigens through direct infection (direct MHC-I presentation pathway) or through the acquisition of exogenous antigens by phagocytosis of virally infected cells or viral particles (cross-presentation pathway). Efficient cross-priming is easily demonstrated in mouse models with an impaired direct antigen presentation pathway (1-3). In addition, genetic deletion of the CD103 + lung DC subset that excels in cross-priming revealed that these cells control the priming of naive CD8 + T cells during influenza virus infection (4) or Sendai virus infection (5). However similar to lymphoid tissue CD8 + DCs, CD103 + DCs are also very potent at direct priming of CD8 + T cells (6) (J. Helft and M. Merad, unpublished observations), suggesting the possibility that the reduced CD8 + T cell responses (4, 5) resulted from the loss of direct antigen presentation normally provided by infected CD103 + DCs. Thus the physiological contribution of cross-presentation to the induction of anti-influenza virus CD8 + T cell immunity in vivo is still a matter of deb-ate.Attempts to generate recombinant fluorescent influenza viruses have been hampered because most of the viruses expressing reporter genes have reduced levels of replication and do not show significant pathogenesis in mice (7). In this study, we visualized the route of viral antigen uptake by lung and LN DCs and examined the antigenic presentation pathway used by DCs to induce efficient CD8 + T cell immunity upon intranasal influenza virus infection.

Visualizing the Beta Interferon Response in Mice during Infection with Influenza A Viruses Expressing or Lacking Nonstructural Protein 1

“…5). It is likely that the disappearing CD11c ϩ cells are dendritic cells which migrate to draining lymph nodes soon after contact with viral antigen, as recently demonstrated by others (30,31). Those authors further demonstrated that the migratory dendritic cells were not productively infected with influenza virus, which explains why IFN production by these cells was not inhibited by virus-encoded NS1.…”

Influenza virus-induced lung injury: pathogenesis and implications for treatment

“…In the presence of inflammatory cytokines released from the lung epithelium and inflammatory cells, e.g. those produced by inflammasome (IL-1β and IL-18) or granulocyte-macrophage colony-stimulating factor (GM-CSF) [110][111][112][113], they are induced to migrate to the draining lymph nodes. In the lymph nodes, CD103 + DCs serve as potent antigen-presenting cells for the activation of naïve CD8 + and CD4 + T-cells and for the presentation of viral antigens to rare virus-specific memory T-cells required for adaptive immunity [114,115].…”

Selective and efficient generation of functional Batf3-dependent CD103+ dendritic cells from mouse bone marrow

“…8,9,37 Antigen uptake represents an important factor that can modulate antigen presentation. CD103 1 DCs take up antigens less efficiently than CD103 -DCs.…”

“…37 Notably, iCD103-DCs and GM-DCs also cross-present cell-associated OVA, albeit with slightly reduced efficiency compared with lung CD103…”