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Prepublished online as a Blood First Edition Paper on January 2, 2003; DOI 10.1182/blood-2002-10-3063.
IMMUNOBIOLOGY
From the Laboratory of Molecular Neuro-Oncology, and
the Laboratory of Cellular Physiology and Immunology, Rockefeller
University, New York, NY; and the Department of Immunology,
DNAX Research Institute, Palo Alto, CA.
Plasmacytoid dendritic cells (pDCs) contribute to innate
antiviral immune responses by producing type I interferons
(IFNs) upon exposure to enveloped viruses. However, their role
in adaptive immune responses, such as the initiation of antiviral
T-cell responses, is not known. In this study, we examined interactions
between blood pDCs and influenza virus with special attention to the
capacity of pDCs to activate influenza-specific T cells. pDCs were
compared with CD11c+ DCs, the most potent
antigen-presenting cells (APCs), for their capacity to activate
T-cell responses. We found that like CD11c+ DCs,
pDCs mature following exposure to influenza virus, express CCR7, and
produce proinflammatory chemokines, but differ in that they produce
type I IFN and are resistant to the cytopathic effect of the infection.
After influenza virus exposure, both DC types exhibited an equivalent
efficiency to expand anti-influenza virus cytotoxic T lymphocytes
(CTLs) and T helper 1 (TH1) CD4+ T cells.
Our results pinpoint a new role of pDCs in the induction of antiviral
T-cell responses and suggest that these DCs play a prominent role in
the adaptive immune response against viruses.
(Blood. 2003;101:3520-3526) There are 2 main dendritic cell (DC)
subsets that have been identified in humans: the CD11c+
myeloid DCs, which include Langherans cells and dermal and interstitial DCs, and the CD11c The involvement of pDCs in the adaptive antiviral immune responses,
especially antiviral T-cell responses, has not been demonstrated. For
instance, pDCs' ability to acquire, process, and present viral antigens to T cells after virus exposure has not yet been addressed. However, several observations suggest that pDCs, after being in contact
with virus, may play a role in the initiation of antiviral T-cell
responses. Indeed, immature pDCs are poor T-cell stimulators, whereas
pDCs matured by HSV or influenza virus expand allogeneic naive T cells
as efficiently as mature CD11c+ DCs.7,8 pDCs
exposed either to CD40L or to influenza virus express CCR7 and migrate
in response to CCL19, a chemokine produced in the T-cell area of lymph
nodes.9,10 Furthermore, pDCs are found in increased number
in secondary lymphoid organs during inflammation.11
In this study, we investigated the effects of influenza virus exposure
on blood-purified pDCs in vitro and the capacity of these cells to
acquire and present viral antigens to CD8+ and
CD4+ T cells. We found that, unlike CD11c+ DCs,
pDCs are resistant to influenza virus infection, characterized by
reduced virus-induced apoptosis and influenza protein expression. However both types of DCs have an equivalent ability to induce the
proliferation and the differentiation of anti-influenza CTLs and T
helper 1 (TH1) CD4+ T cells. Therefore, pDCs likely
play an important role in the initiation of antiviral T-cell responses
via several mechanisms: through production of IFN- T cells, pDCs, and CD11c+ DC purifications
pDC and CD11C+ DC culture
Phenotype DCs were stained with FITC-conjugated mAbs against HLA-DR (Iotest, Beckman Coulter, Miami, FL), CD83 (Pharmingen, Franklin Lakes, NJ), CD86 (Pharmingen), PE-conjugated mAb against CD123 (Pharmingen), or the respective FITC- or PE-conjugated isotype control mAbs (Pharmingen). For CCR7 expression, pDCs were stained with mAb against CCR7 (Pharmingen) followed by a biotin anti-mouse IgM (Pharmingen) and then PE-conjugated streptavidin (Pharmingen). For influenza matrix protein (MP) intracellular staining, DCs were fixed with phosphate-buffered saline (PBS) containing 4% paraformaldehyde and stained with a mAb against influenza MP protein (HB64; ATCC) and an FITC-conjugated goat antimouse mAb (Biosource, Camarillo, CA) in the presence of 0.1% saponin. Fluorescence was analyzed by flow cytometry on a FACScan using Cell Quest Software (BD).CCL19 migration assay IL-3 pDCs or influenza virus-infected pDCs (5 × 104) were incubated in 100 µL RPMI containing 5% PHS in the upper chamber of a transwell 24-well plate with 5.0-µM pore size (Corning, Somerset, NJ). The lower chamber contained 500µL of RPMI containing 5% PHS with or without 25 ng/mL CCL19 chemokine (R&D). After 2 hours, cells in the lower chamber were harvested and counted.DC/T-cell clone coculture Flu16, an HLA-A*0201-restricted MP(58-66)-specific CD8+ T-cell clone, and HA136, a DR 1*0101/DR *0401-restricted influenza HA(307-319)-specific CD4+ T-cell clone, were
isolated and cultured as previously described.12 Then, 105 Flu pDCs, Flu CD11c+ DCs,
peptide-pulsed IL-3 pDCs, and CD11c+ DCs were cocultured
with or without 105 Flu16 or HA136 T-cell clone, in a
96-well U-bottom plate in 200 µL RPMI and 5% PHS. After 24 hours, 50 µL supernatants was collected and tested for IFN- by ELISA
(Pharmingen). After 3 days, 4 µCi/well (0.148 MBq)
3H-thymidine was added for 12 hours. Cells were then
harvested to assess proliferation.
Expansion of HLA-A*0201-restricted influenza MP(58-66)-specific memory CTLs Flu pDCs, Flu CD11c+ DCs, 1 µM MP peptide-pulsed IL-3 pDCs, or CD11c+ DCs (2 × 104) were cocultured with 2 × 105 autologous T cells in 96-well U-bottom plate in 200 µL Yssel medium (Gemini Bio-Products, Woodland, CA) containing 20 µg/mL gentamicin, 1 mM HEPES, and 5% PHS. Then, 7 days later, part of the T cells were washed and stained with a PE-conjugated tetramer of MP(58-66)/HLA-A*0201 or LMP2/HLA-A*0201 complexes and an FITC-conjugated CD8 mAb (BD). Fluorescence was analyzed by flow cytometry. The other portion was restimulated by T2 cells pulsed with or without 10 µM MP peptide in IFN-, IL-4, and IL-10 enzyme-linked
immunospot (ELISPOT) assays to measure the expansion of
MP-specific CTLs as previously described.13 In some
experiments, cytolytic activity of these T-cell populations was
assessed by a standard chromium 51 (51Cr) release
assay using T2 cells as target cells, as previously described.13
Expansion of influenza A virus-specific memory CD4 T cells Flu pDCs or Flu CD11c+ DCs (2 × 104) were cocultured with 2 × 105 autologous T cells in 96-well U-bottom plate in 200 µL Yssel medium (Gemini Bio-Products) containing 20 µg/mL gentamicin, 1 mM HEPES, and 5% PHS. Autologous monocytes were cultured with IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) for 7 days, and monocyte-conditioned medium was added at day 5 to obtain monocyte-derived matured DCs, as previously described.14 Then, 7 days later, T cells were restimulated by monocytes derived from matured DCs infected or not with influenza virus in the presence of 10 µg/mL brefeldin-A (Sigma, St Louis, MO). After 6 hours, cells were stained with a PE-cy5-conjugated mAb against CD4 (Caltag) and then fixed with PBS containing 4% paraformaldehyde and stained with PE-conjugated mAbs against IFN-, IL-4, or IL-10
(Pharmingen) in the presence of 0.1% saponin. Fluorescence was
analyzed by flow cytometry.
Maturation of pDCs and CD11c+ DCs by influenza virus To evaluate pDC and CD11c+ DC interactions with influenza virus, DCs were purified from PBMCs by a 2-step procedure.7 DCs were first pre-enriched by magnetic bead depletion of monocytes, NK cells, erythrocytes, and B and T cells resulting in the removal of 88.7% (± 4.2%) of PBMCs. pDCs (CD3 , CD11c, CD14,
CD16, CD20, and CD4+) and
CD11c+ DCs (CD3, CD11c+,
CD14, CD16, CD20, and
CD4/+) were then purified from the enriched
population by flow cytometry sorting. Yields of pDCs and
CD11c+ DCs were 0.124% (± 0.026%) and 0.216%
(± 0.114%) of the starting population of PBMCs, respectively.
Reanalysis of pDCs and CD11c+ DCs showed a purity of 99%.
Furthermore 100% of pDCs expressed CD123 (Figure
1A).
We cultured pDCs and CD11c+ DCs with different quantities
of influenza virus to evaluate effects of infection. Both types of DCs
underwent maturation following virus exposure as noted by increased
expression of HLA-DR, CD83, and CD86 (Figure 1A). However, pDCs were
resistant to the cytopathic effect of influenza virus, whereas
CD11c+ DCs were sensitive, resulting in the death of the
majority of the cells (see forward scatter [FSC]/side scatter [SSC]
dot plot in Figure 1A). In addition, a smaller fraction of
pDCs expressed influenza virus MP compared with the
CD11c+ DCs. Resistance to influenza infection by pDCs is
likely due to their strong production of type I IFN, such as IFN- In addition to IFN- Capacity of pDCs to activate anti-influenza virus CD8+ CTLs and CD4+ T-cell clones Mixed lymphocyte reactions (MLRs) have shown that pDCs exposed either to HSV or influenza virus are as efficient as CD11c+ DCs in amplifying allogeneic T cells, supporting the idea that pDCs activated following virus encounter play an important role in activating and skewing T-cell response.7,8,15 However, pDCs have never been tested to determine whether they acquire and process viral antigens and directly activate virus-specific T-cell responses. By using Flu16, an HLA-A*0201-restricted influenza MP(58-66)-specific CD8+ CTL, clone and HA136, a DR1*0101/DR*0401-restricted influenza HA(307-319)-specific CD4+ T-cell clone, we
addressed whether pDCs previously exposed to influenza virus or
antigens could induce antigen-specific responses. pDCs and
CD11c+ DCs demonstrated the same efficiency to induce
IFN- production and proliferation of both CD8+ and
CD4+ T-cell clones, whether the viral epitopes were
exogenous peptides or were derived from the processing of viral protein
after influenza virus infection (Figures
2-3). In several experiments,
proliferation of both T-cell clones in response to influenza
virus-infected DCs was as strong as or
stronger than the proliferation induced by DCs pulsed with an optimal
dose of peptide. This is probably due to the high degree of maturation
that takes place following exposure of DCs to the virus.
Presentation of influenza virus antigens by pDCs and CD11c+ DCs from a different source of antigens We showed previously that CD11c+ DCs can present influenza-derived antigens from live and nonreplicating influenza virus with equal efficiency.13,16 The nonreplicating virus (heat inactivated at 56°C or ultraviolet irradiated) retains fusogenic capacity allowing entry of the capsid from endosome to cytoplasm, which is then processed and presented to both CD4+ and CD8+ T cells. We compared pDCs and CD11c+ DCs in their capacity to present different sources of influenza antigens: live influenza virus, able to infect and initiate viral protein expression in DCs (Figure 1A); heat inactivated (HI) influenza virus, able to infect DCs, but unable to initiate viral protein synthesis (data not shown); and boiled influenza virus, unable to infect DCs since it has lost its fusogenic capacity. Antigens from boiled influenza virus, however, can be processed by CD11c+ DCs within endosomes to be presented to CD4+ T cells.16Both DC subsets exposed to live or HI influenza viruses demonstrated a
comparable efficiency to present influenza antigens to the
CD4+ and the CD8+ T-cell clones (Figure
4). This result suggests that extensive new influenza virus protein expression is not required within either DC
subset and that viral particles entering the DCs are a sufficient
source of antigen for processing and presentation to T cells.
When exposed to boiled influenza virus, both DC subsets were unable to
present viral antigen to the CD8+ T-cell clone (Figure 4A),
consistent with our earlier finding that boiling disrupts the virus'
fusogenic capacity, hence entry into the cytoplasm. However, in the
same experiment, only the CD11c+ DCs, but not the pDCs,
were able to activate the CD4+ T-cell clone (Figure 4B).
The absence of viral antigen presentation from boiled influenza virus
by pDCs to the CD4+ T-cell clone was first attributed to
the fact that the boiled virus failed to activate IFN- Activation of anti-influenza virus CD8+ CTL memory responses by pDCs and CD11c+ DCs The majority of HLA-A*0201+ individuals have a strong memory CTL response against influenza MP(58-66). Upon re-exposure to influenza virus, this memory CTL response is rapidly activated. Mature CD11c+ DCs are one of the most efficient APCs to activate this response, whereas monocytes are quite inefficient.13,17 To test whether pDCs have the capacity to activate memory cells, T cells from HLA-A*0201+ donors were cultured in vitro with autologous pDCs or CD11c+ DCs previously pulsed with influenza MP(58-66) peptide or influenza virus. After a week, expansion of HLA-A*0201-restricted influenza MP(58-66)-specific CTLs was assessed by PE-conjugated HLA-A*0201/peptide tetramer staining (Figure 5A). A very low fraction of memory influenza MP(58-66)-specific CTLs was detected in T-cell populations cultured alone or with DCs not exposed to influenza antigens. In T-cell populations cocultured with pDCs or CD11c+ DCs previously pulsed with influenza MP(58-66), or infected with influenza virus, memory influenza MP(58-66)-specific CTLs were expanded at least 20-fold. This expansion was influenza antigen-specific since no staining was observed with a PE-conjugated HLA-A*0201/EBV LMP2 peptide tetramer used as a control. Although results varied from one experiment to another, pDCs cultured either with IL-3 and pulsed with peptide or exposed to influenza virus appeared to have a comparable ability to reactivate anti-influenza CTL memory responses with CD11c+ DCs (Table 1).
Since relatively low numbers of antigen-presenting CD11c+ DCs are able to efficiently activate T cells,16-17 we wanted to determine if it was a property shared by pDCs. T cells were cocultured with different quantities of pDCs or CD11c+ DCs that had been pulsed with influenza MP(58-66) peptide or influenza virus. After a week, expansion of HLA-A*0201-restricted MP-specific T cells was measured by tetramer staining. Low numbers of pDCs (1 pDC for 1000 T cells) were as potent as the CD11c+ DCs to reactivate the influenza-specific CTL memory response (Figure 5B-C). This result suggests that a few influenza virus-infected pDCs may be sufficient to expand these antiviral CTLs in vivo. To assess cytokine production, the HLA-A*0201-restricted influenza
MP(58-66)-specific CTLs expanded either by pDCs or
CD11c+ DCs for one week were restimulated with T2 cells
pulsed with influenza MP(58-66) peptide as
antigen-presenting cells in an IFN- A week after stimulation by pDCs and CD11c+ DCs, the
cytolytic activity of the expanded influenza
MP(58-66)-specific CTLs was analyzed using
51Cr-labeled T2 cells as target cells. pDC- and
CD11c+ DC-expanded CTLs showed a comparable
antigen-specific cytolytic activity (Figure 5E). A higher nonspecific
response to unpulsed T2 cells was observed for the CTL population
expanded by influenza virus-infected CD11c+ DCs. This
nonspecific response was also observed in the IFN- Activation of anti-influenza virus CD4+ T-cell memory responses by pDCs and CD11c+ DCs We next determined if pDCs could also activate the anti-influenza CD4+ T-cell memory response. T cells were cultured with autologous pDCs or CD11c+ DCs previously cultured with influenza virus. After a week, expansion of influenza virus-specific CD4+ T cells was assessed by IFN-, IL-4, and IL-10
intracytoplasmic staining using mature monocyte-derived DCs infected by
influenza virus as APCs (Figure 6).
IFN--producing CD4+ T cells were observed in
populations stimulated either by influenza virus-infected pDCs or
CD11c+ DCs. No influenza virus-specific CD4+ T
cells were detected in the unstimulated T-cell population. Furthermore,
expansion of influenza virus-specific CD4 T cells was
also observed (likely to be CD8+ T cells), and this
population was consistently larger than the influenza virus-specific
CD4+ T cells in all experiments. No antigen-specific
production of IL-4 and IL-10 was observed. Collectively, these results
show that after exposure to influenza virus, pDCs efficiently activate TH1 CD4+ and CD8+ CTL anti-influenza
memory responses.
Until now, evidence that pDCs contribute to the induction of
adaptive antiviral immune responses has been only indirect. To the best
of our knowledge, our studies provide the first demonstration of the
capacity of pDCs to process and present influenza antigens, leading to
the activation of virus-specific CTLs and TH1 CD4+ T cells.
Furthermore, our studies confirm previous findings that pDCs
exposed to influenza virus produce IFN- Strikingly, pDCs are comparable to CD11c+ DCs in their
capacity to activate T-cell responses. This was apparent at several levels. Both DC subsets activated Th1 CD4+ T cells and IFN
Given their advantage over myeloid DCs to produce type I interferons and maintain survival through constitutive expression of MxA, we speculate that pDCs play a primary role in the innate and adaptive response to influenza virus, indeed, probably many enveloped viruses. For instance, herpes, Sendai, and HIV-1 viruses all induce the production of type I interferons from pDCs.4-7 The critical role of pDCs in the initiation of innate immunity and antiviral T-cell responses may explain why the reconstitution of the pDC subset in HIV+ patients during antiretroviral therapy correlates with resistance to opportunistic infections.18 Animal models have also demonstrated that intact pDC function is essential for resistance to murine cytomegalovirus.19 The chemokine receptor expression by pDCs as well as their localization
in vivo are in accordance with the concept that pDCs participate in the
cellular immune responses to viruses. Immature pDCs, like immature
CD11c+ DCs, express chemokine receptors (eg, CCR5, CXCR3)
corresponding to inflammatory cytokines (eg, CCL5, CXCL10). They may be
attracted to inflammatory sites in vivo, even if in vitro they do not
migrate in response to these inflammatory chemokines.10
For instance, accumulation of pDCs has been observed in pathologic
tissues from subjects with granulomatous lymphadenitis,20
Kukichi lymphadenitis,21 epithelioid cell
granulomas,22 cutaneous manifestations of systemic lupus
erythematosus,23 and in nasal mucosa during allergic
reactions.24 At the site of inflammation, pDCs
along with their myeloid DC counterparts may conceivably capture
antigens through direct infection or cross presentation, while
receiving additional stimuli that promote maturation (eg, TNF- pDCs, like myeloid DCs, demonstrate a plasticity that is regulated by
their microenvironment. Depending on the circumstances, they can induce
CD4+ helper T-cell responses, cytolytic CD8+
effectors, NK T cells, and even anergic, immunosuppressive T-cell populations.7,8,26,27 pDCs exposed to virus (HSV,
influenza virus) induce TH1 T-cell responses, characterized by
IFN- Besides their role as APCs, the cytokines and chemokines produced by pDCs exposed to viruses would exert significant autocrine and paracrine effects in their microenvironments. Influenza virus induces the production of CXCL8, CXCL10, CCL3, and CCL5 by pDCs, a panel of chemokines also produced by CD11c+ DCs. This virus-specific induction of chemokines may recruit additional pDCs, CD11c+ DCs, and monocytes, as well as other cells, into inflammatory lesions. Type I IFNs released by pDCs would inhibit viral infection of neighboring cells; promote the induction of activated CD8+ and CD4+ T cells into CTLs and TH1 helper CD4+ T cells, respectively; and may even induce the differentiation of DCs from monocytes.28-30 The central issue raised by our studies is whether pDCs can provide a protective function at the level of T cells in chronic viral infection. Given that pDCs are depleted in HIV-1 infection when viral loads are high and CD4 counts are low, it may be useful to consider their mobilization in vivo via factors such as flt-3 ligand or intervention with antigen-pulsed combinations of pDCs and CD11c+ DCs. Indeed it is now feasible to separate these subsets for clinical use, so direct comparisons of the 2 populations will be feasible in the future. Along these lines, the identification of the murine counterpart of pDCs31-33 will elucidate the relationships and function of these cells.
The authors thank Klara Velinzon and Svetlana Mazel for technical expertise.
Submitted October 8, 2002; accepted December 11, 2002.
Prepublished online as Blood First Edition Paper, January 2, 2003; DOI 10.1182/blood-2002-10-3063.
Supported by the National Institutes of Health (NIH) grants AI 44628 and AI 39516 to N.B. and MOI-RR00102 to the Rockefeller University Clinical Research Center; a Burroughs Wellcome Clinical Investigator grant; and Elizabeth Glaser and Doris Duke Foundation Awards to N.B. Funding was also provided by the Academic Medicine Development Company (AMDeC) Foundation of New York City through its "Tartikoff/Perelman/EIF Fund for Young Investigators in Women's Cancers" to M.L. and the ARC (Association Pour la Recherche sur le Cancer) to J.F.F. C.M. is recipient of a Special Fellowship from the Leukemia & Lymphoma Society and of a grant from the Speaker's Fund for Public Health Research awarded by the city of New York.
J.-F.F. and M.G. contributed equally to this work.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Nina Bhardwaj, Laboratory of Molecular Neuro-Oncology, Rockefeller University, 1230 York Ave, New York, NY; e-mail: bhardwn{at}mail.rockefeller.edu.
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Top
Abstract
Introduction
) when exposed to different types of viruses (influenza virus, herpes simplex virus
[HSV], and HIV).
