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Impaired Clearance of Herpes Simplex Virus Type 1 From Mice Lacking CD1d or NKT Cells Expressing the Semivariant V14-J281 TCR¹

Branka Grubor-Bauk^*,, Anthony Simmons, Graham Mayrhofer and Peter G. Speck^2,*

^* Infectious Diseases Laboratories, Institute of Medical and Veterinary Science, and Department of Molecular Biosciences, University of Adelaide, Adelaide, Australia; and Department of Pediatrics, Children’s Hospital, University of Texas Medical Branch, Galveston, TX 77555

	Abstract

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Ag-presenting molecule CD1 and CD1-restricted NKT cells are known to contribute to defense against a range of infectious pathogens, including some viruses. CD1-restricted NKT cells, a distinct subpopulation of T cells, have striking and rapid effector functions that contribute to host defense, including rapid production of IFN- and IL-4, and activation of NK cells. Consideration of the important contributions of innate and adaptive immunity to clearance of HSV prompted us to investigate the role of CD1 and of NKT cells expressing the V14-J281 TCR in the pathogenesis of HSV infection. To address this issue, we compared infection in wild-type mice with that in CD1 gene knockout (GKO) and J281 GKO mice. In this study, we report impaired clearance of virus and viral Ags, and more florid acute infection in mice lacking CD1 (and by inference, CD1-restricted T cells), in comparison with parental C57BL6 mice. In J281 GKO mice there was also impairment of virus clearance, resembling that seen in CD1 GKO mice. These results imply roles for the V14-J281 subset of NKT cells and for CD1d in control of HSV infection.

	Introduction

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Natural infection with HSV involves skin or mucous membranes and the nervous system. In the peripheral nervous system (PNS),³ primary sensory neurons, which are found in dorsal root ganglia (DRG), are the target for HSV and they may undergo either productive or latent infection. Productive infection of sensory neurons generates the potential for lethal spread of virus through the nervous system, but in immunocompetent hosts, viral replication is terminated by timely development of an adaptive immune response (1). The infection of DRG that follows cutaneous inoculation of the flanks of mice with HSV provides a well-characterized model of PNS infection (2). In this model, clearance of infectious virus from the PNS is dependent on CD8⁺ cells, by a mechanism that does not involve destruction of infected neurons (3), while control of virus replication in the skin appears to involve the activities of CD4⁺ T lymphocytes (for a review, see Ref. 4).

Recent studies indicate that a novel subset of T cells, termed NKT cells, which share some surface molecules with NK cells, are important in the early stages of the immune response to a number of infectious agents (5, 6, 7, 8, 9, 10, 11, 12). A subset of these cells appears to recognize Ags presented by CD1 (13). This prompted us to examine the potential role of CD1 in control of HSV disease.

CD1 molecules are MHC class I-like transmembrane glycoproteins that are encoded by a family of genes located outside of the classical MHC loci (14). CD1 molecules have the ability, apparently unique among Ag-presenting molecules, to bind and present lipid and glycolipid Ags (reviewed in Ref. 15) as well the synthetic glycolipid -galactosylceramide (-GalCer) (16), in addition to hydrophobic peptides. CD1 is required for the development of a subset of specialized T cells, termed NKT cells, which express the semivariant V14-J281 TCR paired with V8.2-7 or -2 (17). Like other NKT cells, this subset expresses certain NK cell receptors (members of the NKR-P1 and Ly-49 families) on their surfaces (reviewed in Ref. 18). When stimulated through their TCR, NKT cells rapidly produce a variety of cytokines such as IFN- and IL-4 (19). Much of the interest in NKT cells stems first from their potential to produce IL-4 during innate responses (20) and second, from their recognition of lipid structures presented by CD1 molecules (17). CD1 and/or NKT cells have been implicated in immunity to a number of pathogens. For example, protection of mice against the malaria parasite Plasmodium yoelii has been shown to involve NKT cells (10, 11). IFN- production by NKT cells appears to be important in the protective immune response to Toxoplasma gondii (12), and NKT cells are important for clearance of hepatitis B virus (HBV) from hepatocytes in HBV Ag-expressing transgenic mice treated with -GalCer (21). Thus it appears likely that CD1, possibly through its importance in the development and activation of NKT cells, is important in immunity to a considerable range of pathogens that includes viruses.

In this study, we investigated the role of CD1 molecules and NKT cells in the immunopathogenesis of HSV-1 by using CD1d gene knockout (GKO) or J281 GKO mice of the normally resistant C57BL6 background. Because the alternative CD1d2 variant in mice is nonfunctional (22, 23, 24), mice lacking the CD1d1 isoform lack all CD1 function. The availability of these mice affords an opportunity to test the role of CD1 in immunity to HSV. We report that on infection with HSV using the zosteriform model, CD1d GKO mice show increased morbidity, enhanced spread of virus in the nervous system, and greatly diminished clearance of virus from the skin and nervous system. Data derived using J281 GKO mice complemented that obtained with CD1d GKO mice. These findings indicate that CD1 and the V14-J281 subset of NKT cells play an important role in immunity to herpesvirus.

	Materials and Methods

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Virus

A well-characterized low passage oral isolate of HSV type 1, strain SC16 (25), was used. This virus, which is neuroinvasive in mice, was grown and titrated in Vero cells and a cell-free virus suspension of virus was produced by removal of cells and cell debris by low speed (2000 x g, 5 min) centrifugation. Cell-free virus was then stored at -70°C until required.

Mice

Specific pathogen-free C57BL6 control mice were obtained from the animal breeding facility at University of Adelaide (Adelaide, Australia) and kept in specific pathogen-free conditions in the Institute of Medical and Veterinary Science (Adelaide, Australia). Breeding pairs of C57BL6 CD1d-deficient (22) and C57BL6 NKT cell-deficient (TCR J281GKO) (26) mice were a generous gift from Dr. M. Smyth (Peter MacCallum Cancer Institute, Melbourne, Australia). CD1d-deficient mice have been backcrossed onto the C57BL6 background 10 times, while the NKT cell-deficient (TCR J281GKO) mice were backcrossed 9 times onto the C57BL6 background. The C57BL6 strain is the most resistant inbred mouse strain known for resistance to HSV (27, 28).

Infection of mice

The zosteriform model of infection used in this study is as described (29). Briefly, after depilation with Nair (Carter-Wallace, New South Wales, Australia) a 20-µl droplet of virus containing 10⁶ PFU of virus was applied to the flank skin dorsal to the posterior tip of the spleen, corresponding to the tenth thoracic dermatome (T10). Using a 27-gauge needle, the skin was scarified 20 times through the droplet of virus suspension. Infected mice develop a characteristic band-like zosteriform lesion 5–6 days after virus inoculation, indicating spread of virus in the sensory nervous system.

Titration of virus in tissue samples

Skin samples and left thoracic DRG were removed as described (29). Unless otherwise indicated, individual ganglia spanning the sixth through thirteenth thoracic segment of each experimental animal were analyzed. Tissues were homogenized in 1-ml glass tissue grinders (Wheaton Industries, Millville, NJ) and 10-fold dilutions of homogenates were tested for the presence of infectious virus using Vero cells in a standard plaque assay (30).

Immunohistochemical detection of HSV Ags

DRG were fixed at room temperature for 1 h in a freshly prepared paraformaldehyde-lysine-periodate fixative (31). HSV Ags were detected in paraffin-embedded sections of mouse tissue using the peroxidase-anti-peroxidase method as described (2). The primary Ab was rabbit antiserum to HSV-infected cells, binding of which was detected using swine anti-rabbit Ig, followed by rabbit peroxidase-anti-peroxidase conjugate (all from DAKO, Glostrup, Denmark). Nonspecific binding sites were blocked with 10% normal swine serum in TBS before the addition of primary Ab. All Abs were prepared in this diluent. Negative control slides were incubated with diluent instead of primary Ab and were included in each staining run. Peroxidase activity was detected with the substrate 3,3'-diaminobenzidine (0.5 mg/ml, containing 0.1% H₂O₂), which gives rise to brownish-purple staining in positive cells.

	Results

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Disease is more severe in CD1d GKO mice

CD1d GKO mice develop more severe clinical disease than control mice, as shown by development of zosteriform lesions in a greater proportion of mice, and by more prominent skin lesions. As shown in Fig. 1, 27 of 27 CD1 GKO mice developed lesions, compared with 6 of 10 of wild-type control mice. CD1d GKO mice developed notably larger lesions (mean lesion width 7.5 mm) than control mice (mean lesion width 1.5 mm).

View larger version (51K): [in this window] [in a new window]   FIGURE 1. Mice were infected with 106 PFU of the SC16 HSV-1 strain and lesions were examined at 6 days postinfection. Left panel, CD1d GKO mice developed more severe lesions in skin (top) when compared with C57BL6 control (bottom). Right panel, Of all infected mice, skin lesions in CD1d GKO mice (samples 1–27) were two to three times larger than those observed with control C57BL6 mice (samples 28–38). Not all control mice developed zosteriform lesions during the course of infection, while all CD1d GKO mice had zosteriform lesions.

In each of two separate experiments conducted in duplicate, groups of 30 wild-type control and 30 CD1d GKO mice were infected and on days 3, 5, and 7 after inoculation, 10 mice per group were killed and skin encompassing the inoculation site was excised and assayed for viral load (Fig. 2). Clearance of virus from the skin of control mice was rapid, with virus load on day 7 being 1,000-fold less than on day 3. Because the results from the two experiments conducted in duplicate were indistinguishable, the graph shows the composite data from both experiments. This result accords with our previous report that C57BL6 mice clear HSV infection rapidly (32). In contrast, CD1d GKO mice showed no significant clearance of virus over the entire period of examination.

View larger version (11K): [in this window] [in a new window]   FIGURE 2. Viral load in skin taken from CD1d GKO or control mice 3, 5, or 7 days after infection. Mice were inoculated by scarification through a droplet containing 106 PFU HSV-1 strain SC16 on the left posterior flank corresponding to the tenth and eleventh dermatome and at the times indicated, mice were killed and the skin encompassing the inoculation site was excised. Three days postinfection, virus load is similar in either type of mouse while by 5 days, clearance has commenced in control, but not in GKO, mice. By day 7, viral clearance in control mice is prominent, however, there is no evidence of clearance in CD1d GKO mice.

View larger version (15K): [in this window] [in a new window]   FIGURE 3. HSV-1 titers in spinal ganglia of CD1d GKO mice and control C57BL6 mice. Mice were inoculated by scarification through a droplet containing 106 PFU HSV-1 strain SC16 on the left posterior flank corresponding to the tenth and eleventh dermatomes (T10 and T11) and at the times indicated, mice were killed and spinal ganglia were assayed for virus. A, Three days postinfection; virus has spread through the PNS of CD1d GKO mice, with slower spread and lower viral titer observed in control B6 mice. B, Five days postinfection; at this time, the peak of infection in the skin, >10-fold more virus is recovered from ganglia of CD1d GKO mice compared with controls. C, On day 7 postinfection, rapid viral clearance is observed in controls, while in CD1d GKO mice, virus persisted at a higher titer. Error bars, derived from means of 20 mice at each timepoint, are wider for the wild-type (control) mice because some animals had no virus.

Immunohistochemistry for viral Ags, done on sensory nervous tissue, affirms that HSV infection in the peripheral nervous system is more florid in the absence of CD1d. In control mice 7 days after flank inoculation, viral Ag expression was typically either sparse or absent in sectional profiles of DRG, as shown in Fig. 4B. In contrast, in sections of ganglia from CD1d GKO mice (Fig. 4A), expression of viral Ags was abundant, with ganglionic profiles typically showing 20 or more Ag-positive neuronal profiles. It was concluded that 7 days after inoculation, there are more infected neurons in CD1d GKO mice than control mice.

View larger version (160K): [in this window] [in a new window]   FIGURE 4. HSV Ag expression (dark-staining cells) in sensory ganglia of mice 7 days after skin inoculation shows florid infection in CD1d GKO mice (A) compared with wild-type C57BL6 mice (B) in which virus clearance is almost complete, with only one positive cell (arrow).

Greater viral load and impaired virus clearance in J281 GKO mice

CD1d GKO mice lack not only CD1d but also CD1-restricted NKT cells. The rearranged J281 gene contributes to the characteristic V14-J281 TCR found on NKT cells. Therefore, experiments were conducted to measure virus load during acute infection in J281-deficient, but CD1d-replete, mice. Skin taken from inoculation sites during established acute infection (day 5) showed substantially higher viral loads in J281 or CD1d GKO mice compared with wild-type, with log₁₀ PFU (means ± SD, n = 5) of 6.0 ± 0.6, 5.9 ± 0.8, and 4.8 ± 0.2, respectively. To compare the clearance of virus from the DRG in J281 GKO mice, CD1d GKO mice and wild-type mice, groups were infected by skin inoculation and on days 5 and 7 after infection, virus was assayed in the spinal ganglia. On day 5, there is evidence of impaired virus clearance both in J281 GKO and CD1d GKO mice in comparison with control C57BL6 mice. DRG in both mutant strains contained up to 10-fold more virus than ganglia from control mice (Fig. 5A). By day 7, the effect was even more pronounced, with ganglia from J281 GKO and CD1d GKO mice containing up to 100-fold more virus than control mice (Fig. 5B).

View larger version (19K): [in this window] [in a new window]   FIGURE 5. HSV-1 titers in spinal ganglia of B6J281 GKO mice, compared with CD1d GKO and control C57BL6 mice. Mice were inoculated by scarification through a droplet containing 106 PFU HSV-1 strain SC16 on the left posterior flank corresponding to the tenth and eleventh dermatomes (T10 and T11). On days 5 and 7 mice were killed and spinal ganglia were excised and assayed for virus. A, Five days postinfection; at this time, the peak of infection in the skin, 5-fold more virus was recovered from ganglia of B6.J281 GKO mice compared with controls. B, On day 7 postinfection, rapid viral clearance was underway in controls, while in B6.J281 GKO mice, virus persisted at a higher titer, with up to 100-fold more virus present than in control animals. This closely resembles the result observed with CD1d GKO mice. Error bars, derived from means of 20 mice at each timepoint, are wider for control animals because some mice had no virus.

	Discussion

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The results of the study provide new insights into mechanisms of resistance during the early stages of primary HSV infection. They show that lack of the CD1-restricted subset of NKT cells leads to more severe disease, greater spread of the virus, involvement of more dorsal root sensory ganglia and delayed clearance of the virus. The nonclassical MHC-like molecule CD1d has been shown previously to present Ags from a range of pathogens to a subset of NKT cells that expresses the semivariant V14-J281 TCR. These pathogens include mycobacteria (38), the spirochete Borrelia burgdorferi (39), respiratory syncytial virus (9), and hepatitis B virus (40). However, the precise extent to which CD1d participates in immunity to each of these pathogens remains unclear. For example, the outcome of infection with Mycobacterium tuberculosis is similar in CD1d GKO and wild-type mice (41), suggesting that NKT cells do not play a critical role in defense against tuberculosis in mice. In contrast, our study provides two lines of evidence that CD1d and CD1d-restricted NKT cells are important in the control of HSV infection and in clearance of the virus.

The mechanism by which CD1d contributes to herpesvirus immunity remains to be elucidated. However, the similarity in the patterns of infection between the CD1d GKO and the J281 GKO mice suggests that CD1d may present a virus-related Ag to CD1-restricted NKT cells. The work of Bendelac (42) has shown that CD1d is a restriction element for activation of this subset of NKT cells. The Ag presented by CD1d to NKT cells during HSV-1 infection could be a virus-derived hydrophobic peptide Ag, or epitopes derived from glycolipids or polypeptides produced by stressed virus-infected cells. A plausible hypothesis is that in the absence of CD1d, the lack of cytokines normally produced by this particular subset of NKT cells leads to a critical impairment of the early immune response to the virus. Of course, the possibility remains that the defects in virus resistance observed in CD1d GKO and J281 GKO mice are not related.

The absence of CD1d- or of CD1d-restricted NKT cells in the GKO mice used in this study could permit greater viral replication and spread early in the infection. Further, lack of early cytokine production by these cells could also impair the response by classical T cells, in particular the production of virus-specific cytotoxic T cells. It has been shown that the CD1d ligand -GalCer can activate NK and CD8 cells (43) and the defective clearance of HSV-1 as late as 7 days after infection in the two GKO strains used in this study suggests adaptive immunity to the virus may be impaired in the absence of an early response by NKT cells. Deletion of CD1d, with the resulting loss of function of a specific subset of NKT cells, may compromise an important link between the innate and adaptive arms of the immune system.

	Acknowledgments

 
We thank Dr. Masaru Taniguchi for agreeing to our use of J281 GKO mice, and we are grateful to Dr. Mark Smyth for insightful discussions.

	Footnotes

 
¹ This work was supported by Grant 104880 from the National Health and Medical Research Council of Australia. We are grateful for the generous support of a Royal Adelaide Hospital Dawes Scholarship (to B.G.-B.).

² Address correspondence and reprint requests to Dr. Peter G. Speck, Infectious Diseases Laboratories, Institute of Medical Veterinary Science, Frome Road, Adelaide SA 5000, Australia. E-mail address: peter.speck{at}imvs.sa.gov.au

³ Abbreviations used in this paper: PNS, peripheral nervous system; DRG, dorsal root ganglia; -GalCer, -galactosylceramide; GKO, gene knockout.

Received for publication August 22, 2002. Accepted for publication November 26, 2002.

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