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The Journal of Immunology, 2003, 170: 4437-4440.
Copyright © 2003 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Conventional CD8{alpha}+ Dendritic Cells Are Preferentially Involved in CTL Priming After Footpad Infection with Herpes Simplex Virus-11

Christopher M. Smith*, Gabrielle T. Belz{dagger}, Nicholas S. Wilson*, Jose A. Villadangos{dagger}, Ken Shortman{dagger}, Francis R. Carbone{ddagger} and William R. Heath2,{dagger}

* Cooperative Research Center for Vaccine Technology and {dagger} Division of Immunology, Walter and Eliza Hall Institute of Medical Research, and {ddagger} Department of Microbiology and Immunology, University of Melbourne, Victoria, Australia


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 References
 
CTL play a major role in immunity to HSV type 1, but little is known about the priming process. In this study, we have examined the class I-restricted presentation of an immunodominant determinant from HSV-1 glycoprotein B after footpad infection. We have found that the only cell types capable of presenting this determinant in draining popliteal lymph nodes within the first 3 days after infection are the CD11c+CD8{alpha}+CD45RA- dendritic cells. Given that such class I-restricted presentation is essential for CTL priming, this implies that these conventional CD8{alpha}+ dendritic cells are the key subset involved in CTL immunity to this virus.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 References
 
Dendritic cells (DCs)3 are potent APCs and are able to activate naive CTL precursors. Extensive lineage analysis has revealed the presence of at least three subpopulations of conventional DCs within the mouse spleen, and up to five subsets in the lymph nodes (LNs) (1, 2). In addition, the mouse equivalent of the human plasmacytoid DC (pDC) has recently been identified in the spleen and LNs (3, 4, 5). This means there are at least six different subsets of DC that do not seem to be precursor product-related, but are different sublineages. DC can be subdivided by their expression of the surface markers CD8{alpha} (CD8), CD4, CD45RA, and CD205 (1, 2). Although there is extensive evidence for different surface marker and cytokine expression (6, 7, 8, 9), little understanding of the functional differences between the various DC subsets has been achieved.

It might be speculated that different DC subsets are specialized for specific pathogens because of their preferential expression of innate receptors and pattern of cytokine secretion. In addition, the CD8 DCs appear to play a particularly important role in priming the antiviral CTL response because of their ability to acquire Ag from apoptotic cells (10, 11), such as would arise as a consequence of many forms of virus infection. These DCs have been shown to preferentially cross-present model cell-associated Ags to prime CD8+ T cell responses, consistent with the notion that they play a key role in generating antiviral immunity (12). However, while this subset has been shown to preferentially present class I-restricted Ag derived from nonreplicating virus-like particles (13), there is currently no comparable data involving an infectious live virus. In addition, other DC subsets have been implicated in other aspects of antiviral immunity. Most notably, pDCs respond to viruses by producing IFN-{alpha}, which is important for effective antiviral immunity (14, 15).

CTL priming to HSV type 1 infection represents a particular challenge to the immune system because this virus has an array of immune subversion mechanisms. For example, HSV ICP47 directly targets MHC class I-mediated Ag presentation (16, 17), while HSV infection has been shown to down-regulate DC maturation and migration, both necessary for efficient CTL priming (18, 19, 20). Despite these mechanisms CTL appear to be important in anti-HSV immunity (21, 22) as well as potentially playing a key role in maintaining viral latency (23). Given the emerging complexity of DCs in terms of their phenotypic heterogeneity and differential responsiveness to pathogens, we were particularly interested in defining which of the populations were potentially important in anti-HSV CTL priming. In this study, we show that following s.c. infection with HSV, only the CD8 DCs presented MHC class I-restricted Ag, arguing that this is the key DC subset involved in CTL priming to this virus.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
References
 
Mice, viruses, and peptide

C57BL/6 (B6) and gBT-I.1 (gBT-I) mice were bred and kept at The Walter and Eliza Hall Institute of Medical Research (Victoria, Australia), and were maintained in conventional conditions. Mice were used between the age of 6 and 8 wk. The KOS strain of HSV-1 was propagated and titered as previously described (24, 25). For footpad infection, mice were injected s.c. in each hind leg between the footpad and heel with 4 x 105 PFU HSV in 20 µl of PBS. The gBT-I.1 transgenic mice express a TCR that recognizes the HSV-SSIEFARL (glycoprotein B (gB)498–505,) epitope complexed with H-2Kb (26).

Depletion of cell subsets

Popliteal LNs were removed from mice infected with HSV 48 h previously. LN were dissociated into small fragments using a scalpel blade and digested in 0.5 ml of collagenase/DNase solution to form a single cell suspension as described previously (27). The cells were resuspended in balanced salt solution with 5% FCS and 0.1 mM EDTA and with either N418 (anti-CD11c), 53-6.7 (anti-CD8{alpha}), RA3-6B2 (anti-B220), M1/70 (anti-CD11b), KT3 (anti-CD3{epsilon}), or NLDC 145 (anti-CD205) mAb for 30 min at 4°C. The cells were washed once and combined with sheep anti-rat IgG-coupled magnetic beads (Dynabeads M-450; Dynal, Oslo, Norway) at a 3:1 bead-to-cell ratio for 20 min at 4°C and rotated at an angle at 30 rpm. Bead-bound cells were removed using a magnet and the cells contained within the supernatant were recovered.

LacZ-inducible hybridoma assays for measuring Ag presentation by LN cells

The gB498–505-specific hybridoma HSV-2.3.2E2 was produced as previously described (28, 29). Two-fold serial dilutions of the popliteal LN cells were made in 96-well flat-bottom plates starting at 106 cells per well. Hybridoma cells (105) were added to each well before overnight culture. Background lacZ expression was determined using hybridomas alone or with LN cells from uninfected mice. X-gal assays were performed on the cultures to identify the responding hybridomas as described previously (30). Microscopic examination numerating blue cells was done after 8–12 h.

In vitro proliferation assay

Mice were infected with HSV and 48 h later single cell suspensions were generated by collagenase and DNase digestion, as described above. DCs were then purified from the cell suspension as described previously (27). Briefly, the cells were Ab-depleted using a mixture of anti-CD3{epsilon} (KT3), anti-Thy-1 (T24/31.7), anti-CD19 (ID6), anti-Gr-1 (RB6-8C5), and anti-erythrocyte (Ter-119) mAb. The Ab-coated cells were removed with sheep anti-rat IgG-coupled magnetic beads. Immunofluorescent labeling with CD11c (HL3), CD8{alpha} (53-6.7), and CD45RA (14.8) and sorting by FACS using a MoFlo instrument (Cytomation, Fort Collins, CO) were used to complete purification of the DCs into subsets. Two-fold serial dilutions starting at 2.5 x 104 purified cells were cocultured in vitro with 5 x 104 CFSE-labeled gBT-I cells in 200 µl of DMEM (Media Unit, Walter and Eliza Hall Institute of Medical Research) supplemented with 10% FCS, 2 mM L-glutamine (Life Technologies, Grand Island, NY) and 50 µM 2-ME (Sigma-Aldrich, St. Louis, MO) in V-bottom tissue culture plates (Costar, Cambridge, MA). Proliferation was measured as a loss of CFSE concentration determined by flow cytometry after 60 h of culture. To ensure that the same proportion of cells per well were compared between samples, 2.5 x 104 BD PharMingen Sphero Blank calibration particles (San Diego, CA) were added to each well and 1.2 x 104 beads were collected during analysis.

gBT-I T cell purification and CFSE labeling

The gBT-I cells were prepared and purified by generating single cell suspensions of LN cells from gBT-I mice and depleting with mAb against M1/70 (macrophage and DCs), F4/80 (macrophage), Ter 119 (RBC), RB6 (granulocytes), M5/114 (MHC class II), and GK 1.5 (CD4). The Ab-labeled cells were removed by anti-rat IgG-coupled magnetic beads. The gBT-I cells were >95% CD8+V{alpha}2+ cells at this point. These cells were then labeled with 0.5 µM CFSE for 10 min at 37°C.

PCR detection of HSV DNA

DNA from DC subsets sorted from infected mice was purified using DNAzol (Molecular Research Center, Cincinnati, OH) supplemented with proteinase K (250 ng) following the manufacturer’s specifications. LN from mice infected for 2 h and HSV grown in vitro were used as positive controls. Genomic DNA was isolated as described by the manufacturer’s instructions. The HSV DNA was amplified by PCR as described previously, using 40 rather than 35 cycles (31).

Results and Discussion

The HSV-specific CTL response in C57BL/6 mice is largely directed toward a single immunodominant determinant from the glycoprotein B (gB) Ag (25, 32, 33). Presentation of this determinant can be detected by using the gB-specific hybridoma, HSV-2.3.2E2, which produces {beta}-galactosidase after TCR engagement. The presence of APCs can be assessed by simply mixing single cell suspensions derived from the draining LN (DLN) with this T cell hybridoma and developing the cultures with X-gal as reported previously (28). To determine the specific subset of cells responsible for Ag presentation, DLN cells were coated with mAbs specific for various cell surface markers and then depleted by immunomagnetic beads (Fig. 1) before mixing with the T cells. The enzyme digestion used for preparing single cell suspensions is relatively mild and should release all cells from the DLN. Depletion of CD11c+, CD8+ or CD205+ cells abrogated presentation by the DLN cells from infected mice. In contrast, depletion of CD11b+ and B220+ cells or CD3+ cells had no effect on the level of presentation. Combined, the data indicated that the cells presenting gB were not B cells (B220+), T cells (CD3+), macrophages (CD11b+), or Langerhans cells (CD11b+). Moreover, the complete loss of gB presentation after CD11c depletion means that only cells expressing this marker were involved in class I-restricted presentation of the immunodominant gB determinant. Consequently, presentation most likely involves DCs because these are the predominant cells that express this particular molecule within the DLN. The essential role of a bone marrow-derived cell, such as a DC, in priming to HSV was also supported by examining CTL priming in bone marrow chimeras (data not shown).



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  		FIGURE 1. The APC presenting gB is CD8+, CD205+, and CD11c+. Characterization of the APC presenting gB498–505 after infection with HSV. DLNs were taken from B6 mice 2 days following HSV footpad infection. Single cell suspensions were prepared and depleted of specific cell subsets using anti-rat IgG-coupled magnetic beads to specifically remove Ab-labeled cells. These depleted preparations were then used to stimulate the gB498–505-specific hybridoma. All three panels represent individual experiments that depleted various different subsets of cells. LN cells (5 x 105) were used per well. Pooled data from two to three experiments, each performed in duplicate, are depicted as mean values and their SDs.

 
The finding that anti-CD8{alpha} and anti-CD205 abolished class I-restricted gB presentation (Fig. 1) narrowed the possible subset of DCs involved in this event. Although originally the expression of CD8{alpha} was used to mark DCs thought to be of lymphoid origin (1, 34), it is now clear that this surface Ag is expressed on a variety of quite different DC subsets. We were interested in two particular subsets expressing CD8 that have been implicated in either CTL priming (12, 13, 35) or antiviral immunity (5, 14). The first is the conventional CD8 DC subset identified by Vremec et al. (1) and which has recently been shown to be important in cross-presentation of Ag for both CTL priming and tolerance (12, 29). These cells express CD205 but not CD11b, consistent with the cells responsible for Ag presentation in Fig. 1. The second population are the pDCs, a subset that can express CD8 under some circumstances (27, 36). The pDCs were also of particular interest because we found a preferential influx of these cells into DLNs after footpad immunization with HSV (Fig. 2 and data not shown). However, these cells are B220+ and CD205- (27, 36), which does not correlate with the APCs in Fig. 1.



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  		FIGURE 2. CD8{alpha} and CD45RA expression by LN DCs before and after infection. Flow cytometric analysis of DC subsets (gated on CD11c+ cells) in the popliteal LN of naive B6 mice (upper panel) or mice infected 2 days previously with HSV (lower panel). Single cell suspensions were prepared and depleted of all non-DCs using an Ab mixture followed by anti-rat IgG-coupled magnetic beads. The DCs were stained with CD11c, CD8{alpha}, and CD45RA Abs and sorted into CD11c+CD45RA+ (pDC), CD11c+CD8{alpha}+CD45RA- (CD8 DCs), and CD11c+CD8{alpha}-CD45RA- (DN DCs). Numerical values within regions represent percentages of the total.

 
Conventional CD8 DCs can also be distinguished from pDCs on the basis of CD45RA expression, these are CD45RA- and CD45RA+, respectively. To determine which of these subsets was involved in presentation of the HSV Ag, we examined the response of CD8+ T cells from the gB-specific TCR transgenic line gBT-I to various purified DCs sorted as in Fig. 2 on their differential expression of CD8{alpha} and CD45RA. The use of transgenic T cells allowed us to show that presentation was capable of activating naive T cells, which have more stringent activation requirements than the immortalized T cell hybridomas used in Fig. 1. Two days after footpad infection of B6 mice, LN cells were isolated, enriched for DC, and then sorted into three CD11c+ DC subsets (Fig. 2). These comprised 1) CD8{alpha}highCD45RA- cells, which are the conventional CD8 DCs, 2) CD8{alpha}+/-CD45RA+ cells, whichencompass all the pDC, and 3) CD8{alpha}-CD45RA- cells (double-negative (DN) DC), which take in all remaining DC subsets. The sorted cells were cultured with CFSE-labeled gBT-I cells in vitro to assess induction of T cell proliferation (Fig. 3). The results show that only the CD8{alpha}+CD45RA- DCs were able to stimulate naive gB-specific T cells, arguing that no other DC subset contributes to the class I-restricted T cell activation within DLN after footpad infection.



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  		FIGURE 3. Only CD8 DC are capable of priming naive T cells during primary HSV infection. DCs were isolated from the DLNs of B6 mice infected with HSV in the footpad. After the time periods indicated, cells were isolated and CD11c+ cells were sorted into CD8 DC, pDC, and DN DC populations based on CD8{alpha} and CD45RA expression. Sorted DCs (2.5 x 104) were cocultured with 5 x 104 CFSE-labeled gBT-I cells in vitro. Following culture CD8{alpha}+V{alpha}2+ gBT-I cells were analyzed by flow cytometry for proliferation. Each time point was performed at least twice. Histograms represent the number of gBT-I cells per 12,000 beads for each sample. In cases where there is no response, naive T cells survive quite poorly. In one experiment, mice expressing OVA under the class II promoter were infected in the footpad with HSV and then DC subsets were isolated from the DLN at 48 h. In this case, all DC subsets were able to stimulate proliferation of OVA-specific CD8 T cells from the OT-I transgenic line (data not shown).

 
It has recently been suggested by Moron et al. (13) that the CD8 DCs may evolve from CD8-CD11b+ precursors that can, themselves, present class I-restricted Ag early after priming. We had previously shown that gB presentation appears within DLN within 6 h after footpad infection (28). Given this, we examined presentation by the three DC subsets over the period from 6 to 72 h after infection (Fig. 3). The results show that only the CD8+CD45RA- DCs present the gB determinant at all times examined.

Although we do not formally prove that presentation of the gB determinant by the CD8+CD45RA- DC leads to HSV-specific CTL immunity in this study, the circumstantial evidence that this is the case is quite compelling. Our approach examines all DC subsets within the draining popliteal LN, which is the site of HSV-specific CTL priming after footpad infection (24). We have previously shown that HSV-specific CTL activation occurs around 6 h after infection, at a time when we observe good presentation of the gB determinant by CD8+CD45RA- DCs (Fig. 3). Moreover, only the CD8+CD45RA- DC present the dominant gB determinant within the first 3 days after infection, during the period necessary for precursor CTL activation and maturation to fully armed effector cells (28). Given this, and the reality that priming requires this presentation, then no other subset could be involved in CTL priming under the conditions examined in this study, although it could be possible that other subsets become involved when other routes of infection are used.

The conventional CD8 DCs involved in CTL priming to HSV-1 are different from the CD11b+ DCs recently implicated in the Th cell response to HSV-2 (37). How these cells overcome HSV evasion strategies such that they are the only cells involved in presentation of the MHC class I-restricted gB determinant in the DLNs remains unresolved at this point. An attractive explanation is that these DCs do not themselves harbor replicating virus, but present Ags derived from infected cells by the process of cross-presentation (38). Consistent with this, the CD8 DCs are known to preferentially acquire Ag from apoptotic cells for class I-restricted Ag presentation (11) and can selectively cross-prime CTL responses in other systems not involving infectious viruses (12). To determine whether any of the DC subsets contained HSV genomic DNA, PCR was performed on DNA isolated from each DC subset 2 days after footpad infection (data not shown). This indicated that all DC subsets contained some HSV genomic DNA, although a stronger signal was consistently obtained from the CD8 DC subset. Whether such DNA was present as a result of DC infection or due to the capture of virions or viral material from infected cells, however, could not be distinguished.

Regardless of the reason for the preferential involvement of the CD8 DCs, this represents the first definitive identification of a single DC subset that appears critical for the CTL response to a virus infection. It highlights this subset as warranting particular attention in additional experiments on CTL immunity to this and other virus infections.


   Acknowledgments
 
We thank D. Vremec for assistance with Abs, C. Clark, V. Lapis, and staff of the Walter and Eliza Hall Institute of Medical Research Flow Cytometry Facility, K. Jordan, L. Inglis, and J. Langley for technical assistance.


   Footnotes
 
1 This work was supported by grants from the National Health and Medical Research Council of Australia, an Australian Research Council Queen Elizabeth II Fellowship, a Howard Hughes Medical Institute International Fellowship, and the Cooperative Research Center for Vaccine Technology. Back

2 Address correspondence and reprint requests to Dr. William R. Heath, Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Victoria, Australia, 3050. E-mail address: heath{at}wehi.edu.au Back

3 Abbreviations used in this paper: DC, dendritic cell; LN, lymph node; pDC, plasmacytoid DC; DLN, draining LN; gB, glycoprotein B; DN, double-negative. Back

Received for publication January 29, 2003. Accepted for publication March 7, 2003.


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E. Ingulli, C. Funatake, E. L. Jacovetty, and M. Zanetti
Cutting Edge: Antigen Presentation to CD8 T Cells after Influenza A Virus Infection
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The Absence of Lymphoid CD8+ Dendritic Cell Maturation in L-Selectin-/- Respiratory Compartment Attenuates Antiviral Immunity
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J. McGill, N. Van Rooijen, and K. L. Legge
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J. Waithman, R. S. Allan, H. Kosaka, H. Azukizawa, K. Shortman, M. B. Lutz, W. R. Heath, F. R. Carbone, and G. T. Belz
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B. P. Dolan, K. D. Gibbs Jr, and S. Ostrand-Rosenberg
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S. N. Mueller, C. M. Jones, A. T. Stock, M. Suter, W. R. Heath, and F. R. Carbone
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L.-F. Lee, B. Xu, S. A. Michie, G. F. Beilhack, T. Warganich, S. Turley, and H. O. McDevitt
The role of TNF-{alpha} in the pathogenesis of type 1 diabetes in the nonobese diabetic mouse: Analysis of dendritic cell maturation
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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
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Y. Chung, J.-H. Chang, M.-N. Kweon, P. D. Rennert, and C.-Y. Kang
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G.-X. Yang, Z.-X. Lian, K. Kikuchi, Y.-J. Liu, A. A. Ansari, S. Ikehara, and M. E. Gershwin
CD4- Plasmacytoid Dendritic Cells (pDCs) Migrate in Lymph Nodes by CpG Inoculation and Represent a Potent Functional Subset of pDCs
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G. Pollara, M. Jones, M. E. Handley, M. Rajpopat, A. Kwan, R. S. Coffin, G. Foster, B. Chain, and D. R. Katz
Herpes Simplex Virus Type-1-Induced Activation of Myeloid Dendritic Cells: The Roles of Virus Cell Interaction and Paracrine Type I IFN Secretion
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A. T. Stock, S. N. Mueller, A. L. van Lint, W. R. Heath, and F. R. Carbone
Cutting Edge: Prolonged Antigen Presentation after Herpes Simplex Virus-1 Skin Infection
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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
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G. T. Belz, C. M. Smith, D. Eichner, K. Shortman, G. Karupiah, F. R. Carbone, and W. R. Heath
Cutting Edge: Conventional CD8{alpha}+ Dendritic Cells Are Generally Involved in Priming CTL Immunity to Viruses
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R. S. Allan, C. M. Smith, G. T. Belz, A. L. van Lint, L. M. Wakim, W. R. Heath, and F. R. Carbone
Epidermal Viral Immunity Induced by CD8{alpha}+ Dendritic Cells But Not by Langerhans Cells
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