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The Journal of Immunology, 2004, 173: 2241-2244.
Copyright © 2004 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Prolonged Antigen Presentation after Herpes Simplex Virus-1 Skin Infection1

Angus T. Stock*, Scott N. Mueller*,{ddagger}, Allison L. van Lint*,{ddagger}, William R. Heath{dagger} and Francis R. Carbone2,*

* Department of Microbiology and Immunology, University of Melbourne, and {dagger} Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; and {ddagger} Cooperative Research Centre for Vaccine Technology, Brisbane, Queensland, Australia


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
It has been reported that MHC class I-restricted Ag presentation persists for only a short period following infection with certain pathogens, declining in parallel with the emergence of specific CTL activity. We have examined this issue in the case of murine infection with HSV-1. We found that the period of Ag presentation capable of priming naive CD8+ T cells is comparatively prolonged, persisting for at least 7 days after infection, and continuing despite the appearance of localized CTL activity. Ag presentation was abbreviated to 3 or 4 days postinfection by surgical excision of the inoculation site early after infection. This intervention attenuated the size of the primary CTL response, implying that prolonged presentation is necessary to drive maximal CTL expansion. Combined, these data show that, in some types of infection, CTL priming can extend well beyond the first 24–48 h after primary inoculation.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Cellular immunity is initiated by the acquisition and presentation of foreign Ags by professional APC. Although it has been shown that these events commence within hours of infection (1, 2, 3, 4), the duration of Ag presentation remains less well defined. Initial in vitro studies suggested that naive CD8+ T cells require only brief antigenic stimulation, in some cases as little as 2 h, to enter an autonomous program of division and differentiation (5). At face value, this appears consistent with recent in vivo studies that have shown surprisingly transient levels of Ag presentation after infection with certain viruses, bacteria, and parasites (1, 3, 6). In these latter studies, Ag presentation could be detected within hours of infection but appeared to be extinguished variously by a day or two after its initiation. In the case of Listeria monocytogenes infection, the loss of Ag presentation coincided with the emergence of lytic Ag-specific CTL in the lymphoid organ, giving rise to the notion that the period of Ag presentation was controlled by a feedback mechanism involving the lysis of the APCs by the expanding CTL population (6). Given these demonstrations of surprisingly brief periods of presentation, we have examined the kinetics of Ag presentation following skin infection with HSV-1. In this study, we show that Ag presentation capable of priming resting CD8+ T cell continues in the face of strong CTL activity, persisting far longer than articulated in recent studies, and that this prolonged presentation is necessary for maximal virus-specific T cell expansion.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice, virus, and peptides

C57BL/6, gBT-I, gBT-I.1 x B6.SJL-PtprcaPep3b/BoyJ (gBT-I x B6.Ly5.1), and OT-I mice were obtained from Department of Microbiology and Immunology (University of Melbourne). The gBT-I and OT-I TCR-transgenic mice are specific for the H-2Kb-restricted immunodominant HSV-1 epitope gB498–505-SSIEFARL (7) and OVA-derived epitope OVA257–264-SIINFEKL (8), respectively. The KOS strain of HSV-1 was propagated and titered on Vero cells in MEM10 (MEM with 10% heat-inactivated FCS, 23.83 g/L HEPES, 4 mM L-glutamine, 50 µM 2-ME, and antibiotics).

mAbs and flow cytometry

Anti-CD8{alpha}-allophycocyanin (53-6.7), anti-CD45.1-biotin (A20), and streptavidin-allophycocyanin were obtained from BD Pharmingen (San Diego, CA). Anti-CD8{alpha}-FITC (CT-CD8a) was acquired from Caltag (Burlingame, CA). Cells were stained for 20 min on ice and washed in PBS/azide containing 1% BSA. Propidium iodide was added before flow-cytometric analysis on FACSCalibur flow cytometer (BD Biosciences, San Jose, CA).

Virus infections and inoculation site excision

C57BL/6 mice were inoculated either with 4 x 105 PFU of HSV-1 injected s.c. into each hind footpad or with 1 x 106 PFU of HSV-1 after flank scarification. Inoculation by flank scarification is described in detail elsewhere (9, 10). At specified times after HSV-1 flank infection, the inoculation site or the corresponding area on the contralateral flank was excised from anesthetized mice by cutting out a 0.5 x 0.5-cm2 area of full-thickness skin surrounding the site. The wound was closed using 9-mm surgical wound clips (BD Biosciences).

Determination of viral titer in the dorsal root ganglion (DRG)3 after HSV-1 infection

C57BL/6 mice were infected with HSV-1 via flank scarification and sacrificed after 3 days, and the DRGs innervating the infected dermatome (thoracic DRG levels 7–13) were removed, pooled, and frozen at –70°C in MEM10. Samples were thawed at 37°C and homogenized, and the amount of infectious virus in each sample was determined using a standard PFU assay on confluent Vero cell monolayers.

APC detection assay

The lacZ-inducible glycoprotein B (gB)-specific T cell hybridoma HSV-2.3E2 was used for the detection of gB epitope-bearing APCs in individual popliteal lymph nodes after HSV-1 footpad infection as previously described (2). Briefly, 2-fold serial dilutions of collagenase-digested lymph node cells, starting at 106 cells/well, were cultured in 96-well plates with 105 hybridoma cells for overnight culture before performing 5-bromo-4-chloro-3-indolyl {beta}-D-galactoside assays.

In vivo CTL and proliferation assay

Four-hour in vivo CTL assays were performed as previously described (11). For proliferation assays, lymph nodes from gBT-I or OT-I donor mice were harvested, made into single-cell suspensions, and labeled with CFSE (2.5 µM) for 10 min at 37°C. Cells were washed, and 1 x 106 CFSE-labeled lymphocytes were adoptively transferred via i.v. tail vein injections at various times after HSV-1 infection. Sixty hours after transfer, the draining lymph node(s) were harvested and stained with anti-CD8-allophycocyanin. Stained cell suspensions were analyzed by flow cytometry, collecting between 5 x 103 and 1 x 104 CFSE+CD8+ live lymphocytes.

Flow-cytometric analysis of gBT-I expansion

C57BL/6 mice that received 1 x 105 gBT-I x B6.Ly5.1 lymph node cells 1 day earlier were inoculated with HSV-1 via flank scarification. Seven days after infection, mice were sacrificed, and their spleens were removed. Single-cell suspensions were stained with anti-CD8-FITC, anti-CD45.1-biotin, and streptavidin-allophycocyanin. Stained cell solutions were analyzed by flow cytometry, collecting between 5 x 104 and 1 x 105 CD8+ live lymphocytes.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Persisting Ag presentation after HSV-1 infection

We had previously examined Ag presentation in the draining lymph node after HSV-1 infection by using a T cell hybridoma specific for the HSV-1 immunodominant determinant from gB to show that presentation began between 4 and 6 h after footpad infection (2). Using this approach to measure the longevity of Ag presentation after HSV-1 infection, we found that, although reduced from maximal day 2 levels, gB presentation persisted within the popliteal lymph nodes at detectable levels until ~8 days after footpad infection (Fig. 1A). To determine whether this persisting presentation was capable of priming gB-specific CTL precursors, we transferred T cells derived from a gB-specific TCR-transgenic mouse (gBT-I) (7) at progressively later times after footpad infection. These T cell were labeled with CFSE before transfer, and the dilution of fluorescence intensity signifying proliferation was assessed by flow cytometry 60 h after transfer. Fig. 1B shows that strong proliferation could be detected in the draining lymph node when T cells were transferred as late as 5 days after footpad infection, and some level of presentation appeared to persist until at least day 7 after footpad infection.



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  		FIGURE 1. Ag presentation persists for at least 7 days after HSV-1 infection. C57BL/6 mice were infected with HSV-1 in the hind footpad. a, One to 9 days after infection, the draining popliteal lymph nodes were harvested and assayed for the presence of gB-presenting APCs using a lacZ-inducible gB-specific T cell hybridoma. Dots represent the total number of lacZ+ cells induced by culture with a single lymph node, and the mean for each time point is plotted as a line. b, At various times after infection, 1 x 106 CFSE-labeled gB-specific TCR-transgenic gBT-I lymph node cells were adoptively transferred into infected recipients. Sixty hours after transfer, mice were sacrificed, and the proliferation of donor CD8+ gBT-I T cells in the draining popliteal lymph node was assessed by flow cytometry for the dilution of their CFSE fluorescence. Histograms are gated on live CD8+CFSE+ lymphocytes, and a representative plot is shown of between three and six mice per time point. Inset values represent the mean and SD for the percentage of gBT-I cells that entered division. Control experiments with the transfer of OVA-specific OT-I lymph node cells resulted in negligible donor T cell proliferation at any of the above time points after HSV-1 infection (data not shown).

 
Early surgical removal of the site of skin inoculation limits the spread of lytic virus infection

In an effort to limit the extent of infection, we used a modified flank scarification model of HSV infection. Infection with HSV results in the initial replication in the epithelium immediately adjacent to the site of inoculation before the movement of the virus into the thoracic DRGs and the ultimate re-emergence of virus along the band of skin innervated by the sensory ganglia to give a band of zosteriform lesions. Surgical excision of the primary inoculation site at progressively earlier times after infection appeared to stop the spread of virus, with lesions failing to develop if surgery was performed before 24–36 h after inoculation (Fig. 2A). Consistent with this, recovery of lytic virus from the DRGs was reduced by >1000-fold if surgery was delayed 24 h after infection, and no replicating virus was detected when skin infection was limited to the first 8 h after inoculation (Fig. 2B). These results argue that the early excision of the site of flank infection limits lytic replication to the site of inoculation and the period of time between inoculation and surgical intervention.



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  		FIGURE 2. Early excision of the inoculation site limits the spread of the lytic infection. C57BL/6 mice were infected with HSV-1 via the flank scarification method of inoculation, and 8, 24, or 48 h later, the inoculation site was surgically excised or left intact (w/o). a, Mice were monitored for the development of lesions on the inoculated flank and photographed 6 days after infection. Arrows represent area of lesion formation. b, The level of infectious virus in the DRGs of mice was measured 3 days after infection. Viral titers were determined using standard PFU assays. Dots represent individual mice, and bars show the average for each time point.

 
Ag presentation continues for days after the cessation of lytic infection, even in the presence of CTL effector activity

Given the preceding results, we used this combination of flank infection followed by skin excision to examine how long presentation persisted after cessation of HSV replication. Persistence of in vivo presentation was again measured using the transfer of CFSE-labeled gBT-I cells at various times after infection. Fig. 3A shows that, in mice whose inoculation site was excised 8 h postinfection, CD8+ gBT-I T cells proliferated strongly in the draining brachial lymph node when transferred 2 days after infection. gBT-I T cells continued to divide, albeit at reduced levels, when transferred 4 days after 8-h infection, whereas T cell proliferation was only marginally above background levels when transferred 7 days after infection in 8-h excision mice. If surgical excision was conducted 24 h postinoculation, gBT-I T cells proliferated strongly in the day 4 transfer mice, and low-level donor cell proliferation was observed when transferred 7 days after infection. Thus, in manipulated mice, Ag presentation capable of driving strong proliferation of donor gBT-I T cells continued in the draining lymph node for another 4 days after the surgical clearance of the lytic HSV-1 infection. In comparison, intact control mice continued to support strong proliferation of gBT-I cells transferred 7 days postinfection (Fig. 3A), reinforcing that presentation is long lived if infection is allowed to run its normal course.



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  		FIGURE 3. Ag presentation persists for 3 days after the loss of virus even in the presence of strong CTL activity. C57BL/6 mice were infected with HSV-1 via flank scarification method of inoculation, and 8 or 24 h later, the inoculation site was surgically excised or left intact (w/o). a, At various times after infection, 1 x 106 CFSE-labeled gB-specific TCR-transgenic gBT-I lymph node cells were adoptively transferred into infected recipients. Sixty hours posttransfer, mice were sacrificed, and the division of donor CD8+ gBT-I T cells in the draining brachial lymph node was determined by flow cytometry for the dilution of their CFSE fluorescence. Histograms are gated upon live CD8+CFSE+ lymphocytes, and a representative plot is shown of five to seven mice per time point. Inset values represent the mean and SD for the percentage of gBT-I cells that entered division. Mean background cell division in the absence of infection was 6% with 4% SD. b, The level of anti-gB cytolytic activity present in the draining brachial lymph node was measured 4 days after flank infection using a 4-h in vivo CTL assay. Shown is the average of six to eight mice per group, with error bars representing SD.

 
Wong and Pamer (6) found that the emergence of CTL activity marked the cessation of presentation after L. monocytogenes infection. Using an in vivo CTL assay, we had previously detected strong levels of killing by day 3 following footpad infection (11), whereas Fig. 1 shows that presentation clearly persists well beyond this time after footpad infection. Given this, we wanted to formally determine whether Ag presentation also coexisted with HSV-1-specific CTL activity following flank skin infection in either intact mice, or animals with surgically abbreviated infections. Fig. 3B shows that strong gB-specific CTL activity was indeed present in draining brachial lymph nodes at day 4 postinfection in all mice regardless of surgical intervention. Thus, class I-restricted Ag presentation persists in the face of a strong in vivo CTL response following flank infection, and in the case of control mice, for many days after appearance of CTL activity.

Prolonged Ag presentation is required to prime maximal CTL response

To determine what effect curtailing presentation had on overall CD8+ T cell expansion, mice were infected after flank scarification, and 2, 8, or 24 h later, their inoculation site was surgically excised or left intact. The expansion of a limiting number of gBT-I CD8+ T cells, transferred 1 day before infection, was measured in the spleen 7 days after primary infection (Fig. 4). We found that mice whose inoculation site was excised within 2 h of infection failed to drive any expansion of gB-specific T cells, implying that a minimal infection period is required for any T cell priming to occur (Fig. 4A). However, if surgery was delayed until 8 or 24 h after infection, mice generated robust gB-specific CTL responses, with gBT-I T cells representing 5 and 6% of splenic CD8+ T cells, respectively, by day 7 postinoculation. Despite this strong expansion following short-term infections, these populations were less than half the size of those generated by full-term infection, where gBT-I T cells expanded to 14% of CD8+ T cells. Control mice that had surgery on the contralateral flank generated similar CTL responses to those of intact controls (Fig. 4B). The diminished CTL response after early surgical clearance of the lytic infection seen in Fig. 4A was therefore not a consequence of surgery alone, but a result of limiting the duration of infection and Ag presentation, suggesting that a relatively extended period of presentation was required for optimal T cell expansion following HSV-1 skin infection.



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  		FIGURE 4. An infection period of >24 h is required to prime maximal CTL response. A total of 1 x 105 gBT-I x B6.Ly5.1 lymph node cells was adoptively transferred into congenic C57BL/6 recipients 1 day before HSV-1 infection via the flank scarification method of inoculation. a, At 2, 8, or 24 h postinfection, the inoculation site was surgically excised or left intact (w/o). b, At 2 h postinfection, the corresponding area of skin to the inoculation site on the contralateral flank was excised (excision) or left intact (w/o). Seven days after infection, the proportion of splenic CD8+ T cells of gBT-I origin was assessed by flow cytometry on the basis of Ly5.1 and CD8 expression. Shown is the percentage of splenic CD8+ T cells that are of gBT-I origin, with averages from 6 to 16 mice per time point and error bars representing SD. Statistical significance between truncated (2, 8, or 24 h) and wild-type infections (w/o) was assessed using Student’s t test, and values are shown: *, p < 0.05; **, p < 0.02; or ***, p < 0.01.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We have found Ag presentation capable of driving resting CD8+ T cells into cycle persists in the draining lymph node for at least 7 days after skin infection with HSV-1. Although a similar period of prolonged presentation has been reported following Sendai virus infection (12), a number of more recent studies have found the corresponding period to be far more abbreviated (1, 3, 6). Although our use of relatively large numbers of transgenic T cells may have accentuated the effect of residual presentation, an identical approach showed presentation to last only 3 days after L. monocytogenes infection despite ongoing bacterial replication (6), and even shorter periods of presentation were reported after infection with malaria and vaccinia virus (1, 3). In contrast, our findings fit with a model where the duration of Ag presentation is prolonged, persisting beyond the life of the primary lytic infection. Indeed, we show that a cutaneous HSV-1 infection that lasted for only 8 h, maintained some level of class I-restricted Ag presentation for another 4 days within the draining brachial lymph nodes.

Following L. monocytogenes infection, the cessation of class I-restricted presentation coincided with the acquisition of effector capabilities by the Ag-specific CTL pool (6), leading to the suggestion that presentation is transient due to the CTL-mediated clearance of APC. In this study, we see presentation persisting well beyond the peak of CTL activity, arguing that class I-restricted Ag presentation is not extinguished by armed effector T cells in this infection. This is not to say that CTL can play no role in reducing the level of presentation, and indeed, CTL feedback may explain the drop from its observed day 2 maximum following footpad infection. Nonetheless, presentation can persist in the face of quite robust CTL activity, and to a level that appears to have some effect on the final size of the immune response.

At this point, we are unable to explain why different infections result in either prolonged or abbreviated presentation but believe that it may reflect a fundamental difference in mechanisms of CTL priming. One possibility might be a differential role of CD4+ T cells in the respective responses, because these T cells can protect dendritic cells (DCs) from CTL-mediated killing (13). Alternatively, prolongation of presentation in the case of HSV-1 infection may reflect sequestration of Ag in a manner not directly accessible to CTL. In this respect, HSV-1-specific CTL priming appears to exclusively involve class I-restricted presentation by lymph node-resident CD8+ DCs, suggesting that migrating skin DCs may primarily act as nonpresenting Ag carriers (9, 14). This nonpresenting status makes these skin DCs insensitive to CTL elimination, which combined with their prolonged survival (15), could mean that they act as a relatively long-lived reservoir that maintains presentation for some time after the cessation of lytic HSV-1 infection.

Unlike other infectious models (3, 16), we have found that an extended period of presentation is required for the optimal level of CTL expansion. This is perhaps not surprising in the context of a localized viral infection, where T cell activation occurs exclusively within those lymph nodes draining the site of infection. Given this anatomical restriction, presentation beyond the first day or two after infection may be required to ensure the complete scanning of the entire T cell repertoire needed to recruit the maximal number of naive CTL precursors from the circulation. In contrast, a more disseminated infection, for example, L. monocytogenes and malaria, might have ready access to a large T cell pool, requiring a shorter period of presentation for optimal T cell priming. In addition, given that T cells are retained within the draining lymph node over the course of many divisions (11, 17), it remains possible that persisting presentation during this period results in extended or repeated T cell stimulation necessary for optimal cell survival, expansion, oracquisition of full effector function (18, 19).

In summary, we have found that Ag presentation is relatively prolonged following HSV-1 infection, even in the absence of continuing replication and in the face of local Ag-specific CTL activity. Prematurely aborting Ag presentation was found to attenuate the size of the ensuing CTL response, implying that persisting presentation has some immunological relevance, at least in terms of generating maximal CTL expansion.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by grants from the National Health and Medical Research Council of Australia. W.R.H. is a Howard Hughes International Fellow. Back

2 Address correspondence and reprint requests to Dr. Francis R. Carbone, Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, 3010, Australia. E-mail address: fcarbone{at}unimelb.edu.au Back

3 Abbreviations used in this paper: DRG, dorsal root ganglion; gB, glycoprotein B; DC, dendritic cell. Back

Received for publication March 9, 2004. Accepted for publication June 22, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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