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Both conventional and interferon killer dendritic cells have antigen-presenting capacity during influenza virus infection.

ABSTRACT: Natural killer cells are innate effector cells known for their potential to produce interferon-gamma and kill tumour and virus-infected cells. Recently, B220(+)CD11c(int)NK1.1(+) 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.

SUBMITTER: GeurtsvanKessel CH

PROVIDER: S-EPMC2747012 | biostudies-literature |

REPOSITORIES: biostudies-literature

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IFN-producing killer dendritic cells are antigen-presenting cells endowed with T-cell cross-priming capacity.

Project description:IFN-producing killer dendritic cells (IKDC) represent a recently discovered cell type in the immune system that possesses a number of functions contributing to innate and adaptive immunity, including production of type 1 and 2 IFNs, interleukin (IL)-12, natural killing, and ultimately antigen presentation to naïve T cells. Here, we compared in vitro and in vivo responses of mouse IKDC, conventional dendritic cells (DC), and natural killer (NK) cells to murine cytomegalovirus infection and found distinct functions among these cell subsets. Upon recognition of infected fibroblasts, IKDC, as well as NK, produced high level of IFN-gamma, but unlike NK, IKDC simultaneously produced IL-12p40 and up-regulated MHC class II (MHC-II) and costimulatory molecules. Using MHC-II molecule expression as a phenotypic marker to distinguish activated IKDC from activated NK, we further showed that highly purified MHC-II(+) IKDC but not NK cross-present MHC class I-restricted antigens derived from MCMV-infected targets to CD8(+) T cells in vitro and in vivo. Our findings emphasize the unique nature of IKDC as a killer antigen-presenting cell directly linking innate and adaptive immunity.

| S-EPMC2761009 | biostudies-literature

Antigen Presenting Dendritic Cells

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

Project description: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.

| S-EPMC3484433 | biostudies-literature

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

Project description:CD8+ cytotoxic T cells are critical for viral clearance from the lungs upon influenza virus infection. The contribution of cross-presentation to the induction of anti-viral cytotoxic T cells remains debated. Here, we used a recombinant influenza virus expressing a NS1-GFP reporter gene to visualize the route of antigen presentation by lung dendritic cells (DC) upon viral infection in vivo. We found that lung CD103+ DC are the only subset to carry intact GFP protein to the draining lymph nodes. Strikingly, lung migratory CD103+ DC are not productively infected by influenza virus and thus induce virus-specific CD8+ T cells through the cross-presentation of antigens from virally infected cells. We also show that CD103+ DC resistance to infection correlates with an increased antiviral state in these cells that is dependent on the expression of IFN receptor alpha. In conclusion, these results establish that efficient cross-priming by migratory lung DC is coupled to the acquisition of an anti-viral status, which is dependent on type I IFN signaling pathway.

2013-06-19 | GSE38838 | GEO

Severe H7N9 infection is associated with decreased antigen-presenting capacity of CD14+ cells.

Project description:The outbreak of H7N9 human infection has caused concern worldwide, but the immunological characteristics of infected patients and the determinants of diverse outcomes remain to be thoroughly understood. In this study, twenty-three patients with H7N9 infections were classified into severe and mild cases. We found that severe patients were commonly lymphopenic with significantly lower levels of T cells, monocytes and related cytokine levels compared to the mild cases. The expression of HLA-DR on CD14+ cells were significantly lower in the severe infection group compared to the mild group (in acute phase: 34.65±4.88 vs. 10.37±1.69, p<0.001). Importantly, the expression of HLA-DR on CD14+ cells was negatively correlated with H7N9 infection severity. Furthermore, although the phagocytosis capabilities of monocyte were similar between two groups, the monocytes of severe infection patients had a lower antigen-presenting capacity. And some in vitro experiments suggested that the impaired antigen-presenting function is associated with lower activation of T cells in responses to immune stimulation. Our present study suggested that the severe H7N9 patients were in a state of immune decrease which presented with general lymphopenia and low antigen-presenting capacity resulting in impaired T cell response. Additionally, HLA-DR levels of CD14+ cells may be a potential biomarker for predicting H7N9 disease progression.

| S-EPMC3963940 | biostudies-literature

CD11cloB220+ interferon-producing killer dendritic cells are activated natural killer cells.

Project description:Interferon-producing killer dendritic cells (IKDCs) are a recently described subset of CD11c(lo)B220(+) cells that share phenotypic and functional properties of DCs and natural killer (NK) cells (Chan, C.W., E. Crafton, H.N. Fan, J. Flook, K. Yoshimura, M. Skarica, D. Brockstedt, T.W. Dubensky, M.F. Stins, L.L. Lanier, et al. 2006. Nat. Med. 12:207-213; Taieb, J., N. Chaput, C. Menard, L. Apetoh, E. Ullrich, M. Bonmort, M. Pequignot, N. Casares, M. Terme, C. Flament, et al. 2006. Nat. Med. 12:214-219). IKDC development appears unusual in that cytokines using the interleukin (IL)-2 receptor beta (IL-2Rbeta) chain but not those using the common gamma chain (gamma(c)) are necessary for their generation. By directly comparing Rag2(-/-)gamma(c)(-/y), Rag2(-/-)IL-2Rbeta(-/-), Rag2(-/-)IL-15(-/-), and Rag2(-/-)IL-2(-/-) mice, we demonstrate that IKDC development parallels NK cell development in its strict IL-15 dependence. Moreover, IKDCs uniformly express NK-specific Ncr-1 transcripts (encoding NKp46), whereas NKp46(+) cells are absent in Ncr1(gfp/+)gamma(c)(-/y) mice. Distinguishing features of IKDCs (CD11c(lo)B220(+)MHC-II(+)) were carefully examined on developing NK cells in the bone marrow and on peripheral NK cells. As B220 expression was heterogeneous, defining B220(lo) versus B220(hi) NK1.1(+) NK cells could be considered as arbitrary, and few phenotypic differences were noted between NK1.1(+) NK cells bearing different levels of B220. CD11c expression did not correlate with B220 or major histocompatibility complex (MHC) class II (MHC-II) expression, and most MHC-II(+) NK1.1(+) cells did not express B220 and were thus not IKDCs. Finally, CD11c, MHC-II, and B220 levels were up-regulated on NK1.1(+) cells upon activation in vitro or in vivo in a proliferation-dependent fashion. Our data suggest that the majority of CD11c(lo)B220(+) "IKDC-like" cells represent activated NK cells.

| S-EPMC2118499 | biostudies-literature

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

2013-06-19 | E-GEOD-38838 | biostudies-arrayexpress

Interferon-beta pretreatment of conventional and plasmacytoid human dendritic cells enhances their activation by influenza virus.

Project description:Influenza virus produces a protein, NS1, that inhibits infected cells from releasing type I interferon (IFN) and blocks maturation of conventional dendritic cells (DCs). As a result, influenza virus is a poor activator of both mouse and human DCs in vitro. However, in vivo a strong immune response to virus infection is generated in both species, suggesting that other factors may contribute to the maturation of DCs in vivo. It is likely that the environment in which a DC encounters a virus would contain multiple pro-inflammatory molecules, including type I IFN. Type I IFN is a critical component of the viral immune response that initiates an antiviral state in cells, primarily by triggering a broad transcriptional program that interferes with the ability of virus to establish infection in the cell. In this study, we have examined the activation profiles of both conventional and plasmacytoid dendritic cells (cDCs and pDCs) in response to an influenza virus infection in the context of a type I IFN-containing environment. We found that both cDCs and pDCs demonstrate a greater activation response to influenza virus when pre-exposed to IFN-beta (IFN priming); although, the priming kinetics are different in these two cell types. This strongly suggests that type I IFN functions not only to reduce viral replication in these immune cells, but also to promote greater DC activation during influenza virus infections.

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Loss of Phagocytic and Antigen Cross-Presenting Capacity in Aging Dendritic Cells Is Associated with Mitochondrial Dysfunction.

Project description:Impaired functionality of dendritic cells (DCs) significantly contributes to decreased adaptive immune responses in aged hosts. The expression of MHC-peptide on the DC surface is the critical first step in T cell priming, but few studies have addressed the effect of aging on Ag acquisition, processing, and presentation by DCs. In this study, we show that aged murine DCs were less efficient in the cross-presentation of cell-associated Ag and subsequently in the cross-priming of CD8(+) T cells than were their young counterparts. The decreased cross-presentation was associated with a reduction in the frequency of CD8? DCs and merocytic (CD8?(-)CD11b(-))DCs that could endocytose cell-associated Ag, as well as the number and the size of the endocytosed particles in the DC that did internalize cell-associated materials. Mechanistically, phagocytic capacity has been associated with mitochondrial activity and membrane potential (??m). Aged DCs exhibited profound signs of mitochondrial dysfunction, illustrated by lower ??m, reduced ATP turnover and coupling efficiency, decreased baseline oxidative phosphorylation, and greater proton leak and reactive oxygen species (ROS) production. Mimicking the aged metabolic phenotype in young DCs by pharmacologic manipulation indicated that the reductions in ??m and ATP impeded the phagocytic capacity whereas ROS interfered with a later step in the cross-presentation process. Conversely, in vitro scavenging of ROS partially restored cross-presentation by aged DCs. Taken together, these data suggest that improvement of aged DC functionality might be feasible in the elderly by targeting metabolic dysfunction or its downstream sequelae, thereby opening new avenues for enhancing vaccine efficiency in this population.

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Interferon-?-Induced Dendritic Cells Generated with Human Platelet Lysate Exhibit Elevated Antigen Presenting Ability to Cytotoxic T Lymphocytes.

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