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CUTTING EDGE |
+ Dendritic Cells Are Generally Involved in Priming CTL Immunity to Viruses 1
* Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia;
The Cooperative Research Centre for Vaccine Technology at The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia;
John Curtin School of Medical Research, Australian National University, Canberra, Australia; and
Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia
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Abstract |
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+ DC have been shown to prime immunity to HSV. Whether this very limited capacity of a single DC subset priming CTL immunity is restricted to HSV infection or is a more general property of anti-viral immunity was examined. Here, we show that the CD8+ DCs are the principal DC subset that initiates CTL immunity to s.c. infection by influenza virus, HSV, and vaccinia virus. This same subset also dominated immunity after i.v. infection with all three viruses, suggesting a similar involvement in other routes of infection. These data highlight the general role played by CD8+ DCs in CTL priming to viral infection and raises the possibility that this DC subset is specialized for viral immunity. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Initial analysis has shown that CD8+ DCs are responsible for priming CTL immunity to a s.c. infection of the footpad by HSV (14). We sought to determine whether these DCs played a wider role in class I-restricted presentation after virus infection. To this end, we examined two routes of infection with three different viruses, two large dsDNA viruses, vaccinia, and HSV and a small negatively stranded RNA virus, influenza A virus. We show that CD8+ DCs appear to be involved in CTL immunity irrespective of the inoculation route or the type of virus.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 (B6, H-2b) and TCR transgenic mice were obtained from The Walter and Eliza Hall Institute of Medical Research animal facility (Melbourne, Australia) and were maintained under standard conditions. Experiments with all mice began when they were between 6 and 10 wk of age. gBT-I.1 (H-2b) transgenic mice (gBT-I) express a TCR (V2V
8.1) specific for the immunodominant MHC class I-restricted epitope of HSV glycoprotein B (gB) (gB498–505) (15). OT-I (H-2b) transgenic mice express a TCR (V2V5) that recognizes the MHC class I-restricted epitope of OVA (OVA257–264) (16). Transgenic mice that express OVA in all cells of the body regulated by the actin promoter (Act-mOVA) (17) were used in some experiments.
Mice were anesthetized with methoxyfluorane and then infected with virus diluted in 20 µl of PBS for footpad and 200 µl of PBS for i.v. (tail vein) infection, respectively. Infections were undertaken with KOS strain of HSV or WSN-gB (H1N1) influenza virus, the latter of which contains the gB498–505 Kb-restricted epitope of HSV inserted into the neurominidase stalk (18). For footpad infection, 102.6 PFU WSN-gB, 4 x 105 PFU HSV, or 5 x 106 PFU vaccinia-OVA (vac-OVA, kindly provided by Dr J. Yewdell, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD) was used; for i.v. infection 102.95 PFU WSN-gB, 4 x 104 PFU HSV or 1 x 106 PFU vac-OVA was used.
DC isolation from lymph nodes and spleen
DCs were isolated essentially as described (7, 9). Briefly, popliteal lymph nodes (LNs) or spleen fragments were digested for 20 min at room temperature with collagenase/DNase (1 mg/ml collagenase type II (Worthington Biochemicals, Lakewood, NJ) and 1 µg/ml grade II bovine pancreatic DNase I (Boehringer-Mannheim, Mannheim, Germany)) and then treated for 5 min with EDTA to disrupt T cell-DC complexes. Cells not of the DC lineage were depleted by incubating in predetermined optimal concentrations of purified Abs: anti-CD3 (KT3), anti-Thy1 (T24/31.7), anti-CD19 (ID3), anti-GR-1 (RB6-8C5), and anti-erythrocyte (TER-119) and then removing the Ab-binding cells with anti-rat Ig-coupled magnetic beads (Dynabeads; Dynal, Oslo, Norway). Note that in our hands pDC are not depleted using anti-GR-1 mAb (19, 20). For some preparations of double negative (DN) DC, B220+, and CD8+ populations were also removed by substituting anti-B220 (RA3-6B2) for anti-CD19, and inclusion of anti-CD8 (53-6.7) mAb in the depletion mixture. The DCs in the enriched populations were gated as CD11c+ cells before sorting into specific subsets by fluorescence activated cell sorting (MoFlo instrument; Cytomation, Fort Collins, CO).
CFSE-labeling of transgenic T cells
LNs (inguinal, brachial, axillary, sacral, superficial cervical, iliac, and mesenteric) were obtained from CD8+ TCR transgenic mice (gBT-I or OT-I) and purified using a mixture of optimally titered Abs to deplete cells expressing Mac-1 (M1/70), F4/80, Ter 119, GR-1, MHC class II (M5/114), and CD4 (GK1.5) followed by sheep anti-mouse and anti-rat dynabeads (Dynal). Enriched cells contained 87–96% specific CD8+ TCR transgenic T cells. These were labeled with CFSE (Molecular Probes, Eugene, OR) by incubating 107 purified cells per milliliter with 5 µM CFSE for 10 min at 37°C. Cells were then washed three times in HEPES modified Eagles medium containing 2.5% FCS.
Analysis of in vitro activation of naive T cells by DCs
A total of 5 x 104 CD8-enriched CFSE-labeled TCR transgenic cells were added to 1.25 x 104 fluorescence activated cell sorted DCs in 200 µl mouse tonicity RPMI 1640 containing 10% FCS, 50 µM 2-ME, 2 mM L-glutamine, 100 U/ml penicillin, and 100 µg/ml streptomycin (complete medium) in 96-well V-bottom plates (Costar, Corning, Corning, NY). Each culture was performed in duplicate. Cultures were analyzed for proliferation after 60 h. Cells were stained with anti-CD8-allophycocyanin (53-6.7; BD PharMingen, San Diego, CA) and anti-V2-PE (B20.1; BD PharMingen). CD8+V2+PI- cells from the entire well were analyzed for proliferation by flow cytometry.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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+ DCs
Our previous studies had shown that conventional CD8+ DCs were solely responsible for priming CTL immunity to HSV after s.c. infection (14). We wanted to determine whether other viruses infecting by this same route used the same or different DC subsets. As a general approach to determine the subsets responsible for priming CTL immunity, C57BL/6 (B6) mice were infected with either 1) HSV, 2) a recombinant version of influenza virus, WSN-gB, which expresses the immunodominant class I-restricted epitope from gB of HSV, or 3) a recombinant version of vaccinia, vac-OVA, which expresses OVA. Use of recombinant viruses allowed us to measure presentation of Kb-restricted determinants in B6 mice using naive responding CD8+ T cells from gBT-I or OT-I TCR transgenic mice specific for gB (15) and OVA (16), respectively.
To determine the DC subset(s) involved in priming after s.c. infection with different viruses, B6 mice were infected s.c in the footpad with either HSV, WSN-gB, or vac-OVA. Two days later, at the peak of Ag presentation in the HSV response (21), their popliteal LNs were harvested and DC separated into subsets based on expression of CD8 and CD45RA. This divided the DCs into conventional (CD45RA-) DCs of CD8- or CD8+ phenotypes and the plasmacytoid DCs (CD45RA+) (Fig. 1). These will be termed DN DCs, CD8 DCs, and pDCs, respectively. In this case, the DN DCs contain more than one DC subtype. Each subset from infected mice was examined for the ability to induce proliferation of gBT-I or OT-I CD8+ T cells, depending on the type of viral infection (Fig. 2). CD8 DCs were the only subset capable of stimulating naive gBT-I cells in the case of HSV infection, consistent with our previous findings (14). This was also the case for stimulating immunity to a s.c. infection with recombinant influenza or vaccinia viruses. Thus, CTL immunity to all three viruses was induced by the same DC subset after s.c. infection.
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24 h, with very few present at 48 h. To ensure that by examining presentation at 48 h above (Fig. 2) we had not missed presentation by an alternative DC subset that occurred earlier, we examined the DC subsets responsible of presentation of vac-OVA at 24 h, and in one experiment, at 12 h (Fig. 3). These data indicated that presentation entirely resided with the CD8 DCs even at the earlier time.
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+ DCsExtending these studies to a second priming route (i.v. infection) where we expected all DC subsets might be exposed to virus, surprisingly showed that like footpad infection, only the CD8 DCs primed gBT-I or OT-I cells to proliferate to the respective viruses (Fig. 4A). Failure of other DC subsets to prime proliferation of naive CD8+ T cells during viral infection was not due to an inability to stimulate naive T cells as pulsing of each splenic DC subset with the gB peptide gB498–505 in vitro allowed them to stimulate proliferation of gBT-I cells (Fig. 4B, middle panel). Furthermore, when DCs were isolated from the spleen (Fig. 4B, lower panel) or LNs (data not shown) and then intentionally infected with either WSN-gB or HSV, each DC subset was able to stimulate proliferation of gBT-I T cells. This indicated that each DC subset was capable of presenting viral Ag and suggested that infection does not prevent Ag presentation. To further confirm that infection was not impairing the capacity of the non-CD8 DC to stimulate naive CD8 T cells, we i.v. infected mice that transgenically expressed OVA in all tissues (Act-mOVA mice (17)). DC subsets from the spleens of these HSV-infected mice were then examined for their capacity to stimulate both OVA-specific OT-I cells and HSV gB-specific gBT-I cells (Fig. 4C). Although all DC were able to stimulate the OT-I cells, due to endogenous expression of OVA, only the CD8 DC stimulated gBT-I cells. Combined, the above results showed 1) that CD8 DCs were the only subset involved in priming CD8+ T cells during s.c. or i.v. viral infection, and 2) that the same DCs were involved in immunity to three different viruses.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have extended earlier findings by showing that CD8 DCs play the major role in priming CTL immunity to three very different viruses, influenza virus, HSV, and vaccinia virus, by two different routes of infection (i.v. and footpad). In a recent report, we also showed that CD8 DCs were responsible for priming after HSV infection of the skin epithelium (24). In this case, in vivo studies using chimeric mice clearly excluded a role for Langerhans cells despite their dominant presence in the skin. Together, these findings show that CD8 DCs represent the major DC subset responsible for priming CTL immunity to several types of viral infection.
To date, very little has been reported on the specialization of DC subsets during viral immunity, especially for CTL induction. Moron et al. (25) reported that CD8 DCs were important in the initiation of a CTL response to virus-like particles. In this case, however, these particles were noninfectious and did not synthesize Ag, so how this relates to authentic viral infections is unclear. For HSV-2 infection of the vagina, Zhao et al. (26) reported that a CD11b+ DC subset, and not CD8 DCs, were important for stimulation of CD4+ T cell lines. Why CD8 DCs were not involved in this response might relate to a specific property of HSV-2, the unique route of infection, or the use of CD4+ T cells as the responding population. CD8 DCs are notoriously sensitive to isolation procedures and perhaps, for some sites such as the vaginal draining LNs, are difficult to isolate in a functional state.
Yewdell and colleagues (22) examined the interaction of DCs with specific T cells after infection with vaccinia virus and found that virus-infected DCs formed specific interactions with T cells in the first 6–48 h after infection. Here, we used the same priming route (s.c.) to show that only one subset of DCs, the CD8 DCs, presented viral Ags to naive CD8+ T cells. Whether these correspond to the virus-infected cells reported by Norbury et al. (22) will be of interest.
Together, our findings indicate that CD8 DCs form an important general surveillance system for virus infection. Although it is formally possible that the CD8 DCs play no role in CTL priming for other viral infections, we consider this unlikely given the diverse nature of those viruses examined here. It is also worth emphasizing that our studies do not exclude involvement of other DCs for alternative routes of infections, although we suggest these additional subsets probably work in conjunction with the CD8 DCs that are ubiquitous throughout the secondary lymphoid compartment (6, 7, 8, 9). In fact, in another study 4, we have found that both the CD8 DCs and a novel DC subset, found in the lung-draining LNs but not the cutaneous nodes or spleen, are involved in T cell priming after pulmonary infection. In this case, CD8 DCs are shown to be LN-resident DC, while the novel DC subset traffics from the lung. Thus, it will be interesting to understand how CD8 DCs obtain viral Ags, and whether cooperation between different DC subsets is necessary for their ability to mediate CTL priming.
As there are now at least six murine DC subsets, but immunity to the viral infections examined here primarily involve only the CD8 DC, we are led to speculate that this DC subset may be specialized for viral or intracellular pathogen immunity. Such specialization of DC subsets is consistent with the diversity of pathogen recognition receptors expressed by different DC subsets (27, 28). However, the ability of CD8 DC to target virus infections may relate to their specialized capacity to cross-present cell-associated Ags (29), which would allow the capture of material from virus-infected cells.
We have reported here that three different viruses use the CD8 DC subset to prime naive T cells after s.c. or i.v. infection. For all viruses tested, the same DC subset was responsible for priming, and highlighting the critical importance of understanding the specific functions of each subset in discriminating different pathogens to elicit immunity. This information provides us with the potential to tailor vaccines to target the specific DCs most likely to direct the generation of robust immune responses and thus long-lasting protective memory. At present, there is very little understanding of which DC subsets are involved in immunity to different infectious agents. These studies prompt a more detailed examination of this question.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Drs. William R. Heath or Gabrielle Belz, Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050, Victoria, Australia. E-mail addresses: heath{at}wehi.edu.au or belz{at}wehi.edu.au
3 Abbreviations used in this paper: DC, dendritic cell; LN, lymph node; gB, glycoprotein B; DN, double negative.
4 G. T. Belz, C. M. Smith, K. Shortman, F. R. Carbone, and W. R. Heath. Distinct migrating and nonmigrating dendritic cell populations are involved in MHC class I-restricted antigen presentation after lung infection with virus Submitted for publication
Received for publication November 12, 2003. Accepted for publication December 18, 2003.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-producing NKT response induced with -galactosylceramide-loaded DCs. Nat. Immunol. 3:867.[Medline]
+ dendritic cells are preferentially involved in CTL priming after footpad infection with herpes simplex virus-1. J. Immunol. 170:4437.+ dendritic cells but not Langerhans cells. Science 301:1925.-CD11b+ dendritic cells present exogenous virus-like particles to CD8+ T cells and subsequently express CD8 and CD205 molecules. J. Exp. Med. 195:1233.+ DC correlates with unresponsiveness to imidazoquinolines. Eur. J. Immunol. 33:827.[Medline]
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B. P. Dolan, K. D. Gibbs Jr, and S. Ostrand-Rosenberg Dendritic Cells Cross-Dressed with Peptide MHC Class I Complexes Prime CD8+ T Cells J. Immunol., November 1, 2006; 177(9): 6018 - 6024. [Abstract] [Full Text] [PDF]
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R. W. Carter, C. Thompson, D. M. Reid, S. Y. C. Wong, and D. F. Tough Preferential Induction of CD4+ T Cell Responses through In Vivo Targeting of Antigen to Dendritic Cell-Associated C-Type Lectin-1 J. Immunol., August 15, 2006; 177(4): 2276 - 2284. [Abstract] [Full Text] [PDF]
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R. L. Reinhardt, S. Hong, S.-J. Kang, Z.-e. Wang, and R. M. Locksley Visualization of IL-12/23p40 In Vivo Reveals Immunostimulatory Dendritic Cell Migrants that Promote Th1 Differentiation J. Immunol., August 1, 2006; 177(3): 1618 - 1627. [Abstract] [Full Text] [PDF]
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M. W. Munks, M. C. Gold, A. L. Zajac, C. M. Doom, C. S. Morello, D. H. Spector, and A. B. Hill Genome-Wide Analysis Reveals a Highly Diverse CD8 T Cell Response to Murine Cytomegalovirus J. Immunol., March 15, 2006; 176(6): 3760 - 3766. [Abstract] [Full Text] [PDF]
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 S. Tahara-Hanaoka, K. Shibuya, H. Kai, A. Miyamoto, Y. Morikawa, N. Ohkochi, S.-i. Honda, and A. Shibuya Tumor rejection by the poliovirus receptor family ligands of the DNAM-1 (CD226) receptor Blood, February 15, 2006; 107(4): 1491 - 1496. [Abstract] [Full Text] [PDF]
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A. L. van Lint, L. Kleinert, S. R. M. Clarke, A. Stock, W. R. Heath, and F. R. Carbone Latent Infection with Herpes Simplex Virus Is Associated with Ongoing CD8+ T-Cell Stimulation by Parenchymal Cells within Sensory Ganglia J. Virol., December 1, 2005; 79(23): 14843 - 14851. [Abstract] [Full Text] [PDF]
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J. K. H. Tan and H. C. O'Neill Maturation requirements for dendritic cells in T cell stimulation leading to tolerance versus immunity J. Leukoc. Biol., August 1, 2005; 78(2): 319 - 324. [Abstract] [Full Text] [PDF]
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J. R. Gordon, F. Li, A. Nayyar, J. Xiang, and X. Zhang CD8{alpha}+, but Not CD8{alpha}-, Dendritic Cells Tolerize Th2 Responses via Contact-Dependent and -Independent Mechanisms, and Reverse Airway Hyperresponsiveness, Th2, and Eosinophil Responses in a Mouse Model of Asthma J. Immunol., August 1, 2005; 175(3): 1516 - 1522. [Abstract] [Full Text] [PDF]
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G. T. Belz, K. Shortman, M. J. Bevan, and W. R. Heath CD8{alpha}+ Dendritic Cells Selectively Present MHC Class I-Restricted Noncytolytic Viral and Intracellular Bacterial Antigens In Vivo J. Immunol., July 1, 2005; 175(1): 196 - 200. [Abstract] [Full Text] [PDF]
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Y. Chung, J.-H. Chang, M.-N. Kweon, P. D. Rennert, and C.-Y. Kang CD8{alpha}-11b+ dendritic cells but not CD8{alpha}+ dendritic cells mediate cross-tolerance toward intestinal antigens Blood, July 1, 2005; 106(1): 201 - 206. [Abstract] [Full Text] [PDF]
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 L. Galibert, G. S. Diemer, Z. Liu, R. S. Johnson, J. L. Smith, T. Walzer, M. R. Comeau, C. T. Rauch, M. F. Wolfson, R. A. Sorensen, et al. Nectin-like Protein 2 Defines a Subset of T-cell Zone Dendritic Cells and Is a Ligand for Class-I-restricted T-cell-associated Molecule J. Biol. Chem., June 10, 2005; 280(23): 21955 - 21964. [Abstract] [Full Text] [PDF]
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A. Heit, F. Schmitz, M. O'Keeffe, C. Staib, D. H. Busch, H. Wagner, and K. M. Huster Protective CD8 T Cell Immunity Triggered by CpG-Protein Conjugates Competes with the Efficacy of Live Vaccines J. Immunol., April 1, 2005; 174(7): 4373 - 4380. [Abstract] [Full Text] [PDF]
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A. Lang and J. Nikolich-Zugich Development and Migration of Protective CD8+ T Cells into the Nervous System following Ocular Herpes Simplex Virus-1 Infection J. Immunol., March 1, 2005; 174(5): 2919 - 2925. [Abstract] [Full Text] [PDF]
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A. Bondanza, V. S. Zimmermann, P. Rovere-Querini, J. Turnay, I. E. Dumitriu, C. M. Stach, R. E. Voll, U. S. Gaipl, W. Bertling, E. Poschl, et al. Inhibition of Phosphatidylserine Recognition Heightens the Immunogenicity of Irradiated Lymphoma Cells In Vivo J. Exp. Med., November 1, 2004; 200(9): 1157 - 1165. [Abstract] [Full Text] [PDF]
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A. Singh, J. Svaren, J. Grayson, and M. Suresh CD8 T Cell Responses to Lymphocytic Choriomeningitis Virus in Early Growth Response Gene 1-Deficient Mice J. Immunol., September 15, 2004; 173(6): 3855 - 3862. [Abstract] [Full Text] [PDF]
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G. T. Belz, C. M. Smith, L. Kleinert, P. Reading, A. Brooks, K. Shortman, F. R. Carbone, and W. R. Heath Distinct migrating and nonmigrating dendritic cell populations are involved in MHC class I-restricted antigen presentation after lung infection with virus PNAS, June 8, 2004; 101(23): 8670 - 8675. [Abstract] [Full Text] [PDF]
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