Both Conventional and Interferon Killer Dendritic Cells Have Antigen-Presenting Capacity during Influenza Virus Infection

Corine H Geurtsvankessel,Femke Muskens,Bart N Lambrecht,Albert D M E Osterhaus,Louis Boon,Ingrid M Bergen,Henk C Hoogsteden,Guus F Rimmelzwaan

doi:10.1371/journal.pone.0007187

Corine H Geurtsvankessel, Femke Muskens + Show 6 more

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https://doi.org/10.1371/journal.pone.0007187

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Natural killer cells are innate effector cells known for their potential to produce interferon-γ and kill tumour and virus-infected cells. Recently, B220+CD11cintNK1.1+ NK cells were found to also have antigen-presenting capacity like dendritic cells (DC), hence their name interferon-producing killer DC (IKDC). Shortly after discovery, it has already been questioned if IKDC really represent a separate subset of NK cells or merely represent a state of activation. Despite similarities with DCs, in vivo evidence that they behave as bona fide APCs is lacking. Here, using a model of influenza infection, we found recruitment of both conventional B220− NK cells and IKDCs to the lung. To study antigen-presenting capacity of NK cell subsets and compare it to cDCs, all cell subsets were sorted from lungs of infected mice and co-cultured ex vivo with antigen specific T cells. Both IKDCs and conventional NK cells as well as cDCs presented virus-encoded antigen to CD8 T cells, whereas only cDCs presented to CD4 T cells. The absence of CD4 responses was predominantly due to a deficiency in MHCII processing, as preprocessed peptide antigen was presented equally well by cDCs and IKDCs. In vivo, the depletion of NK1.1-positive NK cells and IKDCs reduced the expansion of viral nucleoprotein-specific CD8 T cells in the lung and spleen, but did finally not affect viral clearance from the lung. In conclusion, we found evidence for APC function of lung NK cells during influenza infection, but this is a feature not exclusive to the IKDC subset.

Highlights

Influenza type A is a cytolytic virus that causes acute respiratory infection of which the clinical outcome can vary greatly
When selecting for CD32CD192B220+ cells, we found two populations of CD11cint cells in steady state conditions, which can be further discriminated into pDCs by expression of the pDC marker bone marrow stromal antigen-2 recognized by the moAb 120G8
Within the B2202MHCIIhiCD11chi Conventional DCs (cDC), there was a loss of the CD11b2 subset, as recently reported, and the remaining CD11bhi dendritic cells (DC) co-expressed 120G8 [23,13]

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Influenza type A is a cytolytic virus that causes acute respiratory infection of which the clinical outcome can vary greatly. NK cells can kill virus-infected cells without prior antigen stimulation [7,8,9] in a process that is controlled by inhibitory and activating receptors, of which the activating natural killer cell receptor (Ncr1) gene product is most crucial during influenza infection [9,10,11] How exactly this innate immune response influences or enhances initiation of adaptive immunity is poorly understood. By expressing a wide array of microbial pattern recognition receptors shared with cells of the innate immune response and at the same time displaying the potential to process and present antigen to naive T cells, lung DCs bridge innate and adaptive immunity [12] During influenza infection, both conventional (cDC) and plasmacytoid (p)DCs exert different functions, but both are necessary to induce an immune response that clears the virus from the lungs and prevents re-infection [13]. Some authors suggest that IKDCs are functionally and developmentally closer to NK cells than to the two best-known DC family members

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