By
From the * Ben May Institute for Cancer Research, Department of Pathology and Committee on
Immunology, University of Chicago, Chicago, Illinois 60637; and the Department of Ophthalmology
Visual Sciences and Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
60612
Increased numbers of T cell receptor (TCR)-/
cells have been observed in animal models of
influenza and sendai virus infections, as well as in patients infected with human immunodeficiency virus and herpes simplex virus type 1 (HSV-1). However, a direct role for TCR-
/
cells in protective immunity for pathogenic viral infection has not been demonstrated. To define
the role of TCR-
/
cells in anti-HSV-1 immunity, TCR-
/
mice treated with anti-
TCR-
/
monoclonal antibodies or TCR-
/
× TCR-
/
double-deficient mice were
infected with HSV-1 by footpad or ocular routes of infection. In both models of HSV-1 infection, TCR-
/
cells limited severe HSV-1-induced epithelial lesions and greatly reduced mortality by preventing the development of lethal viral encephalitis. The observed protection
resulted from TCR-
/
cell-mediated arrest of both viral replication and neurovirulence. The
demonstration that TCR-
/
cells play an important protective role in murine HSV-1 infections supports their potential contribution to the immune responses in human HSV-1 infection. Thus, this study demonstrates that TCR-
/
cells may play an important regulatory role
in human HSV-1 infections.
Herpes simplex virus type 1 (HSV-1) is a neurotrophic
virus that infects mucosal or abraded skin surfaces of
nonimmune individuals (1). The virus replicates and destroys cells at the portal of entry. In addition, the virus infects nerve endings and is transported by retroaxonal flow
to the nucleus of autonomic nervous system neurons in
which it establishes a latent infection. Immunocompromised individuals develop viral encephalitis due to an inability to limit the spread of virus (2). Numerous studies
have demonstrated that both cellular and humoral arms of
the immune system contribute to the recovery from infection; however, T cells are ultimately required to protect
the host (3).
The discovery of TCR- Several reports have shown that HSV-1 seropositive individuals contain elevated numbers of TCR- Media.
TCR- Mice.
All mice used in this study were bred in the University
of Chicago (Chicago, IL) animal barrier facility under specific
pathogen-free conditions. TCR- Virus.
Two different virus strains were used. The F strain of
HSV-1 was used for the footpad infections and the RE strain of
HSV-1 was used for the ocular infections. Both viral stocks were
grown in monolayer cultures of Vero cells overlayed with 199V
medium (22). The stocks were stored frozen at 108-109 PFU/ml
concentrations. The virus was diluted into PBS just before infection.
Infections.
Mice were infected at 5-6 wk of age. Footpad infections were performed by injecting 50 µl of inoculum containing 106 or 107 PFU into a single hind footpad. Corneal infections
of anesthetized mice were performed by scarifying the cornea in a
crisscross pattern using a 30-gauge needle. An inoculum of 3 µl
containing 5 × 104 or 105 PFU of HSV-1 was added and gently
massaged into the cornea. Mice were visually examined for disease progression and survival over the course of the experiments.
Antibodies.
Anti-TCR- Assays of Viral Replication in the Brain.
Corneal-infected mice
were killed at day 35 after infection. The trigeminal ganglia and
brains were aseptically removed and stored frozen in 1 ml of 199 media. Samples were homogenized in a mechanical tissue grinder,
titrated in medium, and plated on Vero cells (22). Plaques were
counted 2 d later.
Immunohistochemical Analysis of Virus Replication in the Trigeminal
Ganglia.
Mice were killed at the indicated time points after corneal infection. Ipsilateral trigeminal ganglions were excised and
processed for frozen sectioning as previously described (21). Frozen and fixed sections were blocked with normal goat serum for
at least 20 min and then incubated with anti-HSV-1 antibody at
37°C for 1 h (or at 4° overnight). The biotinylated secondary antibody was incubated for 30 min at room temperature after extensive washing. The avidin-biotin complex developing reagent
(Vectastain ABC kit; Vector Labs., Inc., Burlingame, CA) was
used to detect antiviral antibody binding. Sections were counterstained with eosin and mounted with a coverslip using Permount.
No positive cells were observed in uninfected trigeminal ganglia.
Statistical differences were assessed by a one-way ANOVA with
Tukey's post test.
Isolation of HSV-1 gI-reactive TCR- HSV-1 gI Stimulation of Expanded TCR- The ability of TCR null mice to respond to
footpad infection with HSV-1 was analyzed. Fig. 1 A shows
that TCR-
To further define the role of TCR-
HSV-1 infection of the cornea results in a widely studied
inflammatory phenomenon termed herpetic stromal keratitis (HSK; 31) characterized by corneal opacity, necrosis,
and ultimately blindness. HSK may be due to autoimmunity. Corneal infection exposes the immune system to a
normally privileged corneal antigen that is cross-reactive with
HSV-1-reactive T cells and results in an autoimmune mediated destruction of the cornea (32). The surviving TCR The virus load in the trigeminal ganglia from ocularly infected mice was analyzed both
at early (day 6) and late (day 20) time points to determine
whether the TCR-
/
cells a decade ago generated
a great deal of interest in this novel T cell subset since it
might manifest a unique role in immune responses. Significant progress towards understanding the development, antigen reactivity, and immunobiology of TCR-
/
cells has
been made (4). Multiple studies have demonstrated that elevated numbers of TCR-
/
cells exist at inflammatory
sites of a variety of human autoimmune disorders and infections (4, 5). In addition, these cells display an activated
phenotype suggesting an important role for these cells during the immune response. In fact, the study of various in
vivo animal models of bacterial and parasitic infections have revealed a critical role for TCR-
/
cells in regulating infection (4). In a bacterial model of infection using Listeria monocytogenes, TCR-
/
cells have a profound impact
on reducing the pathogenic load in the spleen early in the
infection, before TCR-
/
-mediated clearance (9). Similarly, in a parasitic model of Plasmodium falciparum infection,
TCR-
/
cells are critical in regulating the parasitic burden in the liver (10). In contrast, the role of TCR-
/
cells
in host immunity to viral infections is less clear (12). Increased numbers of TCR-
/
cells have been observed in
animal models of influenza and sendai infection, as well as in patients infected with HIV (13). Furthermore, in
these animal models, distinct subsets of TCR-
/
cells are
recruited to the sites of viral replication. However, a direct
role for TCR-
/
cells in regulating these viral infections
has not been demonstrated.
/
cells in
their peripheral blood that are specific for infected cells (16,
17). In addition, we studied a murine TCR-
/
cell clone
from an infected animal that is specific for the HSV-1 glycoprotein, gI (18, 19). These findings suggested that TCR
/
cells may play an important role in HSV-1 immunity.
To test this hypothesis, we assessed the role of TCR-
/
cell-immune responses to HSV-1 in both a footpad and ocular model of HSV-1 infection (20, 21). These studies used
TCR-specific mAbs, TCR-
/
- and TCR-
/
× TCR
/
-deficient mice to specifically target the TCR-
/
cell
population. In both models of infection, the virus replicates
at the site of infection and is transmitted to sensory ganglia
where it establishes latency and, if not regulated, to the
central nervous system where it can cause lethal encephalitis. Our results demonstrate that TCR-
/
cells regulate
HSV-1 infections by controlling the viral replication and
spread, thus preventing viral induced lethal encephalitis.
/
cell cloning experiments were performed
in complete media which consisted of DMEM media containing
10% FCS, 25 µM Hepes, 2 mM glutamine, 100 U penicillin, 100 µg/ml streptomycin, 2 mM nonessential amino acids, and 5 × 10
5 M 2-mercaptoethanol.
/
mice bred to the BALB/c
background were provided by Adrian Hayday (Yale University,
New Haven, CT). A breeding pair of TCR-
/
mice bred to
the C57BL/6 background were obtained from Jackson Labs. (Bar
Harbor, ME). The TCR-
/
mice were provided by Susumu
Tonegawa (Massachusetts Institute of Technology, Boston, MA)
and were bred to the C57BL/6 background at the University of
Chicago. Mutant mice generated in our breeding were identified
by cell-surface immunofluorescence staining of peripheral blood
cells using anti-TCR-
/
(H57-597) and anti-Thy-1 (53-2.1)
mAbs (PharMingen, San Diego, CA) and analyzed on a FACScan®
(Becton Dickinson, Mountain View, CA). In addition, PCR analysis of genomic tail DNA was used to determine the presence of
TCR-constant-
and neomycin genes.
/
mAbs were produced in our laboratory from the GL3 hybridoma (23). The antibody was purified
on protein A-sepharose (Pharmacia, Uppsala, Sweden) and stored
frozen in PBS. Purified control hamster Ig (Cappel, Malvern, PA)
or anti-TCR-
/
mAbs were administered to mice (intraperitoneally) at least 1 d before infection and continued every 7 d
throughout the study at a dose of 250 µg/mouse. Some experiments used PBS treatments instead of hamster Ig. A human serum
with a high titer of anti-HSV-1 antibody was used for immunohistochemical detection of viral coat proteins. The biotinylated
secondary antibody used for immunohistochemistry was Fc
-specific goat anti-human IgG (Jackson Immunoresearch Labs. Inc.,
West Grove, PA).
/
Cells.
TCR-
/
splenocytes were enriched for T cells by antibody- and complementmediated depletion of MHC class II+ cells with a mixture of anti-
heat stable antigen ( J11D) and anti-class II culture supernatants
(25-9-3) plus rabbit complement. This mixture was incubated for
45 min at 37°C and was then subjected to Ficoll-Hypaque gradient centrifugation to remove dead cells. The resultant cells were
plated in 24-well Linbro plates (ICN Biomedicals, Lisle, IL) at a
concentration of 4 × 106 cells/well in the presence of 6 × 105
mitomycin C (40 µg/ml; Sigma Chemical Co., St. Louis, MO)-
treated gI-transfected L cells (19), 5 × 106 irradiated (20Gy)
BALB/c splenic feeder cells, 1 µg/ml purified anti-CD28 mAb,
2,000 U/ml recombinant human (rh)1 IL-6 (Immunex, Seattle,
WA), and 10 U/ml IL-12 (24). This culture was incubated at
37°C in a 7.5% CO2 incubator for 5 d at which time they were
harvested, washed once, and replated in the same conditions as
above except the growth factors were changed to include 50 U/
ml rhIL-2, and 10 ng/ml rhIL-7 (Immunex). After 7 d, the cells
were assayed for specificity. Immunofluorescence analysis shows
that the expanded cells were 100% TCR-
/
positive.
/
Cells.
Cells were
tested for antigen specificity by assaying IFN-
production. Soluble gI was constructed by fusing the ectodomain of HSV-1 gI and
the Ig Fc domain of human IgG as previously described (19). Soluble gIIg stimulation was performed by immobilizing 5 µg/ml
gIIg antigen on plastic wells at 4°C overnight. Wells were washed
three times with 1× PBS, and TCR-
/
cells (105 cells/well)
were incubated at 37°C in 7.5% CO2 incubator for 48 h. IFN-
production was detected by an ELISA (19).
TCR-/
Cells Mediate Host Protection After HSV-1 Footpad Infections.
/
(TCR-
/
cell+) or TCR-
/
(TCR
/
cell+) mice survived HSV-1 infection. In contrast, the
majority of the footpad-infected T cell-deficient TCR-
/
/
/
mice succumbed to a lethal infection as had previously been shown with T cell-deficient nude mice (25). In
addition, the TCR-
/
/
/
mice that eventually succumbed to the infection developed hind limb paralysis during the infection supporting the conclusion that, in the absence of TCR-
/
cells, the virus gains access to spinal
cord tissue. All groups of mice developed lesions at the site
of infection (the footpad); however, only the TCR-
/
/
/
mice, including those that had survived, failed to resolve their lesions (data not shown). These data suggest that,
under these conditions, both TCR-
/
and TCR-
/
cells were able to clear the infection in the absence of the
other T cell subset. Therefore, under conditions of suboptimal TCR-
/
cell responses, TCR-
/
cells can provide
a critical protective role in this infection. In fact, it is likely
that TCR-
/
cells are involved in HSV-1 infections in
normal mice as TCR-
/
cells are recruited to the infected
ganglia as early as day 6 after infection (21).
Fig. 1.
TCR-/
cells regulate HSV-1 infection. (A) TCR null
mice were infected with HSV-1 in the hind footpad and were monitored for survival. TCR-
+/
/
+/
mice, open triangles; TCR-
+/
/
/
mice, closed triangles; TCR-
/
/
+/
mice, open circles; and TCR-
/
/
/
mice, closed circles. All groups of mice contained at least three animals,
and this plot is representative of two separate experiments. (B) TCR-
/
mice were infected with HSV-1 in the cornea and were monitored for
survival. Control hamster Ig-treated TCR-
/
mice, closed circles; anti-
TCR-
/
mAb-treated TCR-
/
mice, open circles. Both groups of
mice contained five animals and this plot is representative of three separate experiments.
[View Larger Version of this Image (12K GIF file)]
/
Cells Mediate Host Protection After HSV-1 Corneal Infection.
/
cells
in HSV-1 pathogenesis, an ocular model of HSV-1 infection
was examined. Corneal infection results in both a lytic infection
in the cornea and in the surrounding skin tissues (periocular
lesions) as well as migration of the virus to the trigeminal
ganglia. The viral replicative cycle as well as the induced
immune response are best characterized in the BALB/c strain
(26). Therefore, since the double knockout mice were
bred to the C57BL/6 background, studies using the corneal model required the use of TCR-
/
mice that had been
bred to the BALB/c background. In this setting, it is impossible to generate double knockout mice. Therefore, the
TCR-
/
cells were depleted using an anti-TCR-
/
mAbs. As seen in Fig. 1 B, TCR-
/
mice treated with
control hamster Ig did not develop encephalitis, whereas
anti-TCR-
/
mAb-treated TCR-
/
mice succumbed
to a disseminated viral infection and lethal encephalitis. Both groups of mice developed periocular skin lesions
around day 10-15 after infection that contained vesicles of
HSV-1 (data not shown). These lesions spread as the infection proceeded, but the control group ultimately resolved
the skin infection by clearing viral induced vesicles and initiating growth of new hair (Fig. 2). The anti-TCR-
/
mAb-treated mice died without resolving the skin lesions,
similar to previous results in the footpad-infected mice.
Fig. 2.
TCR-/
mice recover from HSV-1 infection and heal
their lesions. Elimination of viral-induced vesicles and scabbing as well as
initiation of new hair follicles is evident in the PBS-treated TCR-
/
mouse on the left. In contrast, the anti-TCR-
/
mAb-treated TCR
/
mouse on the right has continued vesicle formation and scabbing that covers the eye. Photos were taken at day 37 after infection from the
same experiment.
[View Larger Version of this Image (86K GIF file)]
/
mice had no evidence of HSV-1-associated corneal
opacity, destruction, or blindness, revealing that TCR-
/
cells do not participate in this autoimmune reaction. These
results are consistent with earlier experiments using nu/nu
mice or CD4- and CD8-depleted mice where HSK does
not develop (25, 28). This experiment, however, proves
that TCR-
/
cells have no role since the nu/nu mutation
and CD4- and CD8-depletion can affect the TCR-
/
cell compartment.
+/
and TCR-
/
Mice.
/
cells regulate HSV-1 replication.
Immunohistochemical analyses were done to determine the
presence of viral antigen using an antiserum that is specific for viral structural proteins expressed during productive
infections. Interestingly, normal mice treated with antiTCR-
/
mAbs, but not PBS, exhibited an increased viral
burden in the trigeminal ganglion at day 6 after infection
(Fig. 3). These results suggested that TCR-
/
cells decreased viral replication early during the infection, when
few TCR-
/
cells were found homing to the trigeminal ganglion (21). Examination of late time points showed that
normal mice completely resolved the lytic virus infection in
the trigeminal ganglion. In contrast, both TCR-
/
mice
treated with control or anti-TCR-
/
mAbs continued to
express viral antigens characteristic of a productive infection in the ganglia at day 21 after infection (data not
shown). Importantly, using a viral plaque assay, the surviving control treated TCR-
/
mice eventually cleared the
lytic infection (day 35 after infection) and had no detectable infectious virus in the brain or trigeminal ganglia. In
contrast, the moribund (day 35 after infection) anti-TCR
/
mAb-treated TCR-
/
mice contained high levels
of systemic infectious virus (Table 1). The prolonged viral
load in the trigeminal ganglia of TCR-
/
mice is consistent with the delayed resolution of skin lesions in these
mice. It is not clear why the virus persists longer in TCR
/
mice. However, clonal expansion of TCR-
/
cells
to protective levels may take longer to occur because the
total number T cells is reduced in the TCR-
null mice
(33). Together, these results suggest that TCR-
/
cells are
both limiting viral replication and restricting its progression
into the brain.
Fig. 3.
The dynamics of HSV-1 replication is different in TCR-+/
and TCR-
/
mice. (A) Quantitation of immunohistochemical staining of
HSV-1 viral antigens in the trigeminal ganglia at day 6 after infection. Two mice per group and three representative sections of each ganglia (six sections
per group) were prepared for immunohistochemical staining. An average of 1,200 neurons were counted for each group. Data are recorded as the percent
of neurons that exhibited specific HSV-1 staining. The differences between the day 6 after infection control and anti-TCR-
/
mAb-treated TCR-
+/
mice, or between the control and anti-TCR-
/
mAb-treated TCR-
/
mice, were statistically significant (P <0.05). (B) Photomicrographs depicting
immunohistochemical staining of HSV-1 antigens in the trigeminal ganglion. Trigeminal ganglia were obtained 6 d after corneal infection from TCR
+/
mice (A and B) and TCR-
/
mice (C and D). Mice received control (A and C) or anti-TCR-
/
mAb (B and D) treatments. Infected neurons,
black arrows; uninfected neurons, white arrows; a cluster of infected inflammatory cells, black arrowhead in B. Original magnification: 100×.
[View Larger Versions of these Images (147 + 13K GIF file)]
Previous results have shown that a single TCR-/
cell clone recognized a HSV-1-encoded glycoprotein, gI.
To determine whether HSV-1 gI-specific TCR-
/
cells
could be isolated from TCR-
/
mice, spleen cells were
cultured with HSV-1 gI-transfected L cell fibroblasts. After
2 wk in culture in the presence of antigen and growth factors, gI-specific TCR-
/
cells could be detected based on
their ability to secrete IFN-
in response to antigen stimulation. Recognition was direct and specific for unprocessed gI (Fig. 4) since immobilized gIIg fusion protein could be
recognized in the absence of antigen-processing cells, just
as the TgI4.4 clone (19). TCR variable region repertoire of
these expanded TCR-
/
cells shows that they were polyclonal (data not shown). Lastly, the expansion of TCR-
/
cells from unimmunized TCR-
/
mice suggests that
there exists a circulating pool of HSV-1-specific TCR-
/
cells. This pool may account for the rapid TCR-
/
cell- mediated HSV-1 neutralization observed at day 6 after infection of normal mice (Fig. 3).
This study provides direct evidence that TCR-/
cells
can respond to and suppress HSV-1 infection. Other viral
infections, such as influenza (13) and sendai (14), induce
increases in the TCR-
/
population after infection.
However, little evidence exists for a direct role in regulating the infection. Therefore, the critical role of TCR-
/
cells in HSV-1 infection of TCR-
/
mice provides direct evidence that TCR-
/
cells are an important regulatory subset of immune cells.
The mechanism of the protective response, such as the
nature of the antigenic ligands and the effector functions
(cytokine production and/or cytolysis) used by the protective TCR-/
cell population, remains to be elucidated.
Importantly, TCR-
/
cells from TCR-
/
mice produced IFN-
production in the trigeminal ganglion after HSV-1 infection (Kodukula, P., R. Sciammas, J.A. Bluestone, and R.L. Hendricks, unpublished observations). In
addition, the isolation of cytolytic, IFN-
-producing, HSV-1
gI-specific TCR-
/
cells, TgI4.4 and the expanded cells,
suggests that TCR-
/
cells can directly recognize viral
antigens and mount antiviral effector function. Finally, preliminary results suggest that the observed protective response is polyclonal since reverse transcriptase-PCR analysis shows that both TCR-V
1.1 and TCR-V
2 transcripts
are present in infected trigeminal ganglia (Sciammas, R., P. Kodukula, R.L. Hendricks, and J.A. Bluestone, unpublished observations).
Antiviral humoral responses have also been shown to
confer important viral neutralizing activity in HSV-1 infections (34). However, we have not been able to detect any
anti-HSV-1 IgG in the serum of infected TCR-/
mice
(Sciammas, R., P. Kodukula, R.L. Hendricks, and J.A.
Bluestone, unpublished observations). These results suggest
that, in contrast to other disease models (35, 36), TCR-
/
cells are not protecting HSV-1-infected mice by providing
B cell help. Therefore, it is striking that the TCR-
/
cells
in TCR-
/
mice are able to regulate HSV-1 pathology
in light of a nonexistent humoral response and a reduced
number of TCR-
/
cells.
TCR-/
cells, including TgI4.4, recognize antigen directly in a MHC-independent manner (19, 37). Intriguingly, this mode of recognition may be useful in regulating
the viral life cycle by interacting with envelope glycoproteins on the surface of infected cells or on the virus itself. In
addition, it has been reported that HSV-1 has the ability to
specifically intervene with efficient MHC class I expression
by inhibiting the TAP complex (38, 39). Therefore, direct
antigen recognition by TCR-
/
cells may circumvent viral intervention of MHC presentation. Secondly, since
HSV-1 is a neurotrophic virus, TCR-
/
cells could be
adept at recognizing antigens directly on central nervous
system neurons that are poor at processing and presenting
antigens in an MHC-restricted manner (40, 41). Thus,
these data suggest that under circumstances where TCR-
/
cell function is compromised, such as in human acquired immunodeficiency syndromes, TCR-
/
cells may be essential to protect the infected individual.
Address correspondence to Jeffrey A. Bluestone, Ben May Institute for Cancer Research, University of Chicago, MC 1089, 5841 S. Maryland Ave., Chicago, IL 60637.
Received for publication 24 March 1997.
R. Sciammas is supported by a National Institutes of Health/National Institute of Allergy and Infectious Diseases interdisciplinary training program in immunology No. 5T32A107090, J. Bluestone is supported by a grant from the National Institutes of Health No. RO1 AI26847, and P. Kodukula, Q. Tang, and R.L. Hendricks are supported by grants from the National Institutes of Health No. EY10359, EY05945, and EY01792.We are grateful to L. Smith and B. Roizman for excellent intellectual and technical support. In addition, we thank J. Stejskal and J. Lohmiller for veterinary support. We also thank A. Hayday and S. Tonegawa for generously providing the TCR gene-targeted mice. We are grateful to Dr. T.F. Gajewski for the rhIL-12. We also thank P. Fields, E. Klotz, and R. Khattri for discussions and critique of the manuscript.
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