Lung CD103+ Dendritic Cells Efficiently Transport Influenza Virus to the Lymph Node and Load Viral Antigen onto MHC Class I for Presentation to CD8 T Cells

Abstract

The uptake, transport, and presentation of Ags by lung dendritic cells (DCs) are central to the initiation of CD8 T cell responses against respiratory viruses. Although several studies have demonstrated a critical role of CD11blow/negCD103+ DCs for the initiation of cytotoxic T cell responses against the influenza virus, the underlying mechanisms for its potent ability to prime CD8 T cells remain poorly understood. Using a novel approach of fluorescent lipophilic dye-labeled influenza virus, we demonstrate that CD11blow/negCD103+ DCs are the dominant lung DC population transporting influenza virus to the posterior mediastinal lymph node as early as 20 h postinfection. By contrast, CD11bhighCD103neg DCs, although more efficient for taking up the virus within the lung, migrate poorly to the lymph node and remain in the lung to produce proinflammatory cytokines instead. CD11blow/negCD103+ DCs efficiently load viral peptide onto MHC class I complexes and therefore uniquely possess the capacity to potently induce proliferation of naive CD8 T cells. In addition, the peptide transporters TAP1 and TAP2 are constitutively expressed at higher levels in CD11blow/negCD103+ DCs, providing, to our knowledge, the first evidence of a distinct regulation of the Ag-processing pathway in these cells. Collectively, these results show that CD11blow/negCD103+ DCs are functionally specialized for the transport of Ag from the lung to the lymph node and also for efficient processing and presentation of viral Ags to CD8 T cells.

NK Cells Regulate CD8+ T Cell Priming and Dendritic Cell Migration during Influenza A Infection by IFN-γ and Perforin-Dependent Mechanisms

“…Another study demonstrated enhanced endocytosis by CD8 + DCs after effective killing of allogeneic cells by NK cells (53). Our data support the latter view by showing that NK cell-mediated killing of infected cells enhanced uptake of influenza A viral Ags by pulmonary DCs, especially the CD103 + DC subset, which was shown to be important in priming the CTL response during influenza A infection (30). This effect of perforinmediated cytotoxicity probably enhanced the pool of apoptotic cell-associated Ags, which are preferentially taken up by pulmonary CD103…”

“…3). Next, we labeled influenza A with the lipophilic dye, DiD, which is attached to the lipid layer of the virus and has previously been used to follow influenza A virus infections in vivo (20,30). DiD is not incorporated into progenitor virus released from infected cells, and DiD therefore allowed us to track Ag uptake by DCs from primary infected cells.…”

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.…”

CD4 T Cell Help Is Limiting and Selective during the Primary B Cell Response to Influenza Virus Infection

“…After natural infection, many cells in the lung become infected (69), and though dendritic cells (DC) can be infected and synthesize virus proteins and can migrate to the draining lymph node (34,35,70,71), there is limited evidence that these DC are able to release intact virions in the lymph node (72,73). Thus, the form of virus protein available for B cell receptor-mediated uptake in the draining lymph node may consist primarily of membrane fragments and proteins released from dying infected cells that either passively drain to the LN or are actively carried by migratory APC.…”

“…In the control group undergoing primary infection without prior CD4 T cell priming, there were no detectable NP-specific CD4 T cells. Interestingly, an apparent depletion of peptide-specific cells from this site occurred in the infected NP peptide-primed group, which may be an indication that central memory cells were recruited to sites of secondary antigen exposure, such as the MLN, the primary site of antigen access after intranasally inoculated respiratory infection (34)(35)(36)(37).…”