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J Virol, July 1998, p. 6169-6174, Vol. 72, No. 7
Departments of Microbiology-Immunology and Pathology,
Northwestern University Medical School, Chicago, Illinois
60611,1 and
Department of Medicine
(Neurology), Shinshu University Medical School, Matsumoto 390, Japan2
Received 20 January 1998/Accepted 2 April 1998
Intracerebral inoculation of susceptible strains of mice with
Theiler's murine encephalomyelitis virus (TMEV) results in
immune-mediated demyelination. Three major T-cell epitopes have
previously been identified within the VP1 (VP1233-250),
VP2 (VP274-86), and VP3 (VP324-37) capsid
proteins in virus-infected SJL/J mice. These epitopes appear to account
for the majority (~90%) of major histocompatibility complex class
II-restricted T-cell responses to TMEV. Interestingly, the effect of
immunization with synthetic peptides bearing the predominant T-cell
epitopes on the course of TMEV-induced demyelination indicates that T
cells reactive to the VP1 and VP2 epitopes, but not VP3, accelerate the
pathogenesis of demyelination. The predominant pathogenic role of the T
cells is verified by similar immunization with the fusion proteins
containing the entire individual capsid proteins. The order of
appearance and level of T cells specific for the individual epitopes
during the course of demyelination are similar to each other. However,
cytokine profiles of T cells from virus-infected mice indicate that T
cells specific for the VP1 (and perhaps the VP2) epitope are Th1,
whereas T cells reactive to VP3 are primarily Th2. These results
suggest that Th1-type cells specific for VP1 and VP2 are involved in
the pathogenesis of viral demyelination induced by TMEV. Thus, a
predominance of Th1-inducing viral epitopes is likely critical for the
pathogenesis of demyelination.
Although the etiology of multiple
sclerosis remains unknown, epidemiological studies and investigations
with experimental animal models have supported a potential role for
viruses as the causative agent for demyelination (2, 10,
11). In particular, intracerebral (i.c.) injection of Theiler's
murine encephalomyelitis virus (TMEV) into susceptible strains of mice
results in a chronic, progressive demyelinating disease that closely
resembles human multiple sclerosis (24, 40). Demyelination
induced by TMEV is associated with a persistent virus infection in the
central nervous system (CNS) (4, 26, 38), and T-cell
responses to viral antigens seem to play a critical role in the
immunopathologic tissue damage induced after viral infection (8,
25). Demyelinating lesions are characterized by an inflammatory
cell infiltrate consisting of predominantly T cells and macrophages
(34), and the course of demyelinating disease correlates
well with the development of a virus-specific, class II-restricted,
delayed-type hypersensitivity response (8, 16). In
addition, TMEV-induced demyelinating disease (TMEV- IDD) is
inhibited after induction of virus-specific tolerance which
down-regulates Th1-type responses (19, 32), further
supporting a critical role for Th1 cells in the pathogenesis of
demyelination. However, it is not clear how TMEV containing multiple
T-cell epitopes can determine the overall Th1 versus Th2 responses.
The specificity of the CD4+ T-cell response induced upon
TMEV infection has only recently been elucidated in the highly
susceptible SJL/J mouse strain. As with most picornavirus infections,
the cellular immune response is directed primarily at the structural proteins which form the icosahedral capsid structure of the virus (reviewed in reference 41). Dominant T-cell
determinants have been mapped within amino acids 233 to 250 of the VP1
capsid protein (45), residues 74 to 86 of VP2
(15), and residues 24 to 37 of VP3 (44). Previous
analyses of bulk T-cell populations induced by either immunization or
infection with TMEV and T-cell hybridomas derived from virus-infected
mice demonstrated that these three viral epitopes account for the
majority of the viral epitopes recognized by T cells induced upon TMEV
infection (45). Such a restriction in the CD4+
T-cell epitopes permits investigation of the role of these individual epitopes in the pathogenesis of demyelination.
Immunization with VP1233-250 or VP274-86
peptide, but not VP324-37, accelerates the onset of
demyelination.
Previous studies have strongly suggested that
TMEV-induced demyelination is mediated by an inflammatory
CD4+ T-cell population specific for viral epitopes. To
further determine the relative role of the individual epitope-specific
T-cell responses in the pathogenesis of TMEV-IDD, virus-infected SJL/J
mice were immunized with peptides containing the major T-cell epitopes
to examine the potential acceleration of the onset and/or increase in
the severity of virus-induced demyelinating disease. SJL/J mice were
infected with a suboptimal i.c. dose of TMEV (BeAn 8386 strain) at 5 days prior to subcutaneous (s.c.) immunization with peptides
representing VP1233-250, VP274-86, and
VP324-37 or a nonspecific control peptide containing
residues 34 to 45 of hen egg lysozyme (HEL). Mice were subsequently
observed for the development of clinical signs of disease (Fig.
1). The data shown in Fig. 1A demonstrate
that immunization with peptides containing VP1233-250 or
VP274-86 can significantly accelerate the onset of
TMEV-IDD. In this particular experiment, the disease incidence was
100% for the VP1233-250- and
VP274-86-immunized mice at 120 days post viral infection,
although the disease incidence was only 50% for the negative control,
HEL34-45-immunized mice (P < 0.05 by
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Role of Individual T-Cell Epitopes of Theiler's
Virus in the Pathogenesis of Demyelination Correlates with
the Ability To Induce a Th1 Response
ABSTRACT
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2 analysis). However, immunization with a peptide
containing VP324-37 did not result in a similar
acceleration in the clinical symptoms of demyelination (Fig. 1). The
disease incidence paralleled the clinical score, suggesting that there
is no significant influence on the degree of symptoms in these mice
(Fig. 1B). Additional experiments using lower peptide doses confirmed
these findings (data not shown). Immunization with
VP324-37 resulted in a recall T-cell proliferative
response to that peptide similar to the levels in other epitope-primed
mice, demonstrating that the inability to accelerate TMEV-IDD with
VP324-37 was not due to the lack of priming for
VP324-37-specific T cells (data not shown).
View larger version (28K):
[in a new window]
FIG. 1.
Effect of immunization with T-cell epitope-containing
peptides on the development of TMEV-induced demyelination. SJL/J mice
from the National Cancer Institute received an i.c. injection of a
suboptimal dose (6 × 104 PFU) of BeAn 5 days prior to
an s.c. injection of 25 µg of either VP1233-250 (20 mice), VP274-86 (9 mice), VP324-37 (10 mice),
or nonspecific control peptide HEL34-45 (17 mice)
emulsified in complete Freund's adjuvant. Mice subsequently received
booster injections with the indicated peptides (25 µg) emulsified in
incomplete Freund's adjuvant 10 days following the first s.c.
injection. The amino acid sequences of the peptides are as follows:
VP1233-250, SASVRIRYK K M KVFCPRP;
VP274-86, QEAFSHIRIPLPH; VP324-37,
PIYGKTISTPSDYM; HEL34-45, FESNFNTQATNR. (A) Mice were
monitored for the development of clinical signs of demyelinating
disease, which included a waddling gait, extensor spasms, paralysis,
and loss of the righting reflex. Results are expressed as the
percentage of mice exhibiting clinical signs of disease at the
respective days post i.c. infection. The disease course (days 43 to
111) in mice immunized with VP1233-250 (P = 0.0003) and VP274-86 (P = 0.003), but
not VP324-37 (P = 0.24), was significantly
different from that in mice immunized with the control
HEL34-45 peptide based on a two-tailed, unpaired
t test. (B) The clinical severity of the above mice was
assessed on a scale of 0 to 2: no signs of clinical disease, 0; mild
gait abnormalities, 1; extreme gait abnormalities and loss of righting
reflex, 2. To compare the severity with the above clinical incidence,
the mean clinical severity of all of the mice in a group was included
in the calculation.
Immunization with capsid protein VP1 or VP2 (but not VP3) accelerates the onset of demyelination. To verify that the VP1233-250 and VP274-86 epitopes are the major pathogenic epitopes of the viral capsid, susceptible SJL/J mice were immunized with UV-inactivated TMEV or glutathione S-transferase (GST) fusion proteins containing individual capsid proteins 5 and 15 days post viral infection. As previously demonstrated (9), immunization of virus-infected SJL/J mice with UV-inactivated TMEV significantly (P = 0.022) accelerated the disease onset (Fig. 2A). The day of disease onset in 50% of the mice immunized with UV-TMEV (DO50) was day 40 post i.c. inoculation, while that of control mice was day 67. Similar immunization with GST-VP1 or GST-VP2 also resulted in significant acceleration (P = 0.046 and P = 0.009, respectively) from control GST-immunized mice, altering the DO50 from day 53 to day 33 or 30 (Fig. 2B). In contrast, mice immunized with GST-VP3 showed no significant (P = 0.87) level of acceleration of disease or difference in DO50 (day 53) compared with control mice. These results clearly demonstrate that immune responses to capsid proteins VP1 and VP2, but not VP3, enhance the disease progression and are consistent with the results obtained with the individual epitopes (Fig. 1). Therefore, the immunity to the predominant Th epitopes involved in the pathogenesis of demyelination appears to represent a great majority of the Th responses for the entire viral capsid proteins.
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Antibody responses cannot account for the differential acceleration of disease induced by immunization with capsid proteins. To further analyze the immunity induced by GST-capsid proteins which differentially affected the course of demyelination, the levels of antibodies specific for the virus and selective major linear antibody epitopes were also assessed (data not shown). All of these immunized mice were able to produce antibodies to the linear epitopes on the respective capsid proteins equally well, including A3A on VP3 in GST-VP3-immunized mice. Therefore, the differential influence of individual capsid fusion proteins on the acceleration of demyelination is not likely due to the lack of antibody response to the respective capsid proteins.
T-cell proliferative responses to the predominant viral epitopes are similar during the course of demyelinating disease. To determine whether there are differences in the T-cell responses to these major epitopes during the initial phase of TMEV-IDD, SJL/J mice were infected i.c. at different time points with the same stock of virus and then the splenic proliferative responses were determined at the same time to minimize experimental variability. As shown in Fig. 3, proliferative responses to UV-inactivated TMEV and peptides containing the predominant T-cell epitopes can be detected as early as 7 days post viral infection. The proliferative response to the whole virus, as well as to the predominant T-cell epitopes, peaked at approximately 2 to 3 weeks postinfection. However, there were no significant differences in the magnitude of the T-cell proliferative responses at any time point with 1 and 10 µM peptides (data not shown for 10 µM peptides). Thus, these results suggest that the levels of T-cell responses to these major epitopes are similar to each other during the initial phases of TMEV-IDD. However, the T-cell proliferative response levels may not directly reflect the frequencies of T-cell precursors toward the epitopes due to the differential T-cell stimulation.
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cpm) ± the standard error of the mean
(mean counts per minute from UV-inactivated-BeAn-stimulated cultures
minus the mean counts per minute from control cultures with
phosphate-buffered saline or the mean counts per minute from
peptide-stimulated cultures minus the mean counts per minute from
HEL34-45-stimulated cultures). The background counts per
minute were similar to each other in cultures with phosphate-buffered
saline or the nonspecific peptide HEL34-45 and ranged
between 3,316 and 8,642 cpm.
Frequencies of precursor T cells reactive to VP1233-250, VP274-86, and VP324-37 are similar. To correlate the level of T-cell proliferative response with the number of T cells specific to a given epitope, the frequencies of T-cell precursors toward individual T-cell epitopes were assessed as described previously (45) at two different time points, 14 and 26 days post viral infection. The frequency of T cells reactive to VP1233-250 (1 in 41,695; 95% confidence interval, 1 in 31,505 to 1 in 61,626) appears to be somewhat lower than that of T cells reactive to VP274-86 (1 in 26,797; 1 in 19,336 to 1 in 43,633) or VP324-37 (1 in 36,559; 1 in 25,693 to 1 to 63,349) at 14 days and become slightly higher at 26 days post viral infection. Collectively, these data demonstrate that VP1233-250, VP274-86, and VP324-37 represent the predominant epitopes recognized by T cells from SJL/J mice and that there are no significant differences in the frequencies of T cells specific for these epitopes during the course of TMEV-IDD. Therefore, the level of stimulation of T cells toward the individual T-cell epitopes is not likely involved in the differential acceleration of demyelination. Taken together, neither the order nor the level of Th responses to these major epitopes appears to play a critical role in the pathogenesis of immune-mediated demyelination.
T cells reactive to VP1233-250 and
VP274-86 are primarily Th1 and those to
VP324-37 are Th2.
Since neither the level nor the
order of T-cell responses to the major epitopes corresponded to the
differential acceleration of demyelination (Fig. 3), the potential
qualitative differences in T-cell responses to the individual epitopes
were assessed (Fig. 4). The production of
several representative cytokines by T cells from TMEV-infected mice at
a preclinical stage (day 13 post viral infection) in response to
peptides containing the predominant T-cell epitopes was analyzed. As
shown in Fig. 4, T cells from virus-infected mice produce significant
levels of a Th1 cytokine, gamma interferon (IFN-
), in response to
peptides containing the T-cell epitopes or to the whole virus. The
level of IFN- produced in response to VP1233-250 was
approximately four- to fivefold higher than the level of IFN-
produced in response to either VP274-86 or
VP324-37 at day 13. The relatively higher level (two- to
threefold) of IFN- produced in response to the VP1233-250 peptide was maintained at 34 days post viral infection (data not shown). However, the Th1 cytokine production in
response to VP274-86 was only slightly higher than that against VP324-37. The proliferative responses to these
three epitopes in these experiments were also very similar (data not shown), strongly suggesting that the increased production of Th1 cytokines in response to the selective epitopes was not due to an
increased expansion of the epitope-specific T cells.
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)
were again observed in response to VP324-37 and the whole virus, compared to those in response to VP1233-250 and
VP274-86. Taken together, the production of a high level
of IFN-, combined with a low level of IL-4, in response to
VP1233-250 and, perhaps, VP274-86 suggests a
key role of these T-cell responses in the pathogenesis of this
inflammatory demyelinating disease.
Production of Th1 cytokines precedes that of Th2 cytokines in the
CNS during the development of demyelinating disease.
To further
understand the T-cell types involved in the pathogenesis of
demyelination, the levels of representative cytokines in the spinal
cords were examined at various time intervals (0, 7, 11, 28, 42, 56, and 70 days) post viral infection (Fig.
5). The IFN- messages were detectable
as early as 11 days and maintained until the last test time point at 70 days. On the other hand, IL-4 and IL-10 messages were detectable only
after 28 days. Therefore, the production of Th2 cytokine messages in
the CNS following viral infection appears to be lower than that of Th1
cytokine messages (IL-2 and IFN-) at the early stage. This result is
consistent with our previous observation (31) confirming the
initial accumulation of Th1 cytokines in the CNS of virus-infected
SJL/J mice. This early accumulation of relatively higher level of Th1
cytokines in the CNS may set an environment favoring the subsequent
immune-mediated inflammatory demyelination.
|
Potential mechanisms and implications of the differential Th1/Th2 responses to individual epitopes. Our results indicate that individual major Th epitopes within a pathogen are able to induce Th1 and Th2 responses independently. However, the mechanism underlying the differential Th1 and Th2 responses to individual epitopes is not clear. Perhaps the predominant VP1 and VP2 (but not VP3) epitopes interact with high affinity to major histocompatibility complex class II molecules and/or are presented at high ligand densities that preferentially induce Th1-type responses (22, 29, 33). Alternatively, only VP324-37 among the major Th epitopes overlaps a predominant linear antibody epitope region (18, 44). Therefore, it is conceivable that T cells recognizing adjacent or overlapping determinants of antibody epitopes are more likely to interact with epitope-reactive B cells for mutual stimulation, leading to B- and T-cell activation. Such an enhanced interaction between B and T cells may preferentially promote Th2 responses, as described previously (14).
Treatment of susceptible strains of mice with antibodies to either class II or CD4 molecules can significantly suppress the demyelination induced by TMEV (13, 16, 42). The adoptive transfer of a CD4+ T-cell line specific for VP274-86 has also been shown to potentiate the demyelination induced by TMEV (16). In addition, the majority of VP1233-250- or VP274-86-specific T cells cloned from the inflammed spinal cords of TMEV-infected mice are of the Th1 type, suggesting that such T cells have infiltrated the CNS (45). It was also previously shown that downregulation of Th1 responses, but not Th2 responses, suppresses the development of TMEV-IDD (19). These data are consistent with the idea that inflammatory Th1-mediated responses are closely involved in the pathogenesis of virally induced demyelination. T cells specific for these viral determinants may recruit and activate macrophages via their inflammatory cytokines, such as tumor necrosis factors (alpha and beta) and IFN-, resulting in destruction of
myelin (8). The production of inflammatory cytokines by
these virus-specific T cells may also mediate various other effects on
the CNS cells within the microenvironment. For example, IFN-
increases the expression of major histocompatibility complex class I
and II molecules on the CNS cell types (3, 43), enabling
such CNS cells to present antigenic determinants to infiltrating T
cells (12). In addition, such an inflammatory Th1 cell type
may also be involved in the destruction of class II-bearing CNS cells
(37, 39), contributing to the pathogenesis of TMEV-IDD and
subsequent autoimmunity to myelin components (28). Thus, Th1
cells specific for VP1233-250 and VP274-86, which are readily found in the CNS (34, 45), are likely to contribute to chronic inflammation, leading to virus-induced
demyelination.
Certain Th2 cytokines (e.g., IL-4 and IL-10) are known to inhibit
cell-mediated inflammatory Th1 responses in vivo (1, 23,
35). The reciprocal regulation of Th1 and Th2 responses is
critical for the resolution or progression of certain infectious disease (17, 30). In addition, Th2 responses involving the production of IL-4 and IL-10 can suppress the development of CNS inflammation associated with autoimmune demyelination, (experimental allergic encephalomyelitis [EAE]) (6, 36), although a
single cytokine effect may not be sufficient (30). Moreover,
recovery from EAE is also associated with the presence of Th2-type
cytokines (20, 21). Aside from the direct downregulation of
pathogenic Th1 responses, Th2 cytokines can also exhibit protective
effects against neuronal cell injury caused by activated microglia
(5). Despite the preferential Th2 response to the VP3
epitope, the level of the Th2 response to this epitope may not be
sufficient to overcome the effect of overall greater Th1 responses to
other viral epitopes such as the VP1 and VP2 epitopes. Thus, it is
conceivable that the ratio of Th1- to Th2-inducing epitopes may
determine the initial type of Th responses to a pathogen
(31) and the consequent pathogenicity of immune-mediated
inflammatory disease. In addition, our preliminary studies indicating
that variant viruses containing a single amino acid substitution within
the VP1 epitope leading to a Th2 response are not pathogenic (data not
shown) reinforce the importance of the ratio of Th1 to Th2 epitopes in the induction of immune-mediated inflammatory disease.
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ACKNOWLEDGMENTS |
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This work was supported by USPHS grants RO1 NS28752 and RO1 NS33008. J.P. is a postdoctoral fellow (FG1172-A-1) of the National Multiple Sclerosis Society.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Microbiology-Immunology, Northwestern University Medical School, 303 East Chicago Ave., Chicago, IL 60611. Phone: (312) 503-8693. Fax: (312) 503-1339. E-mail: bskim{at}nwu.edu.
Present address: Division of Tumor Virology, Dana-Farber Cancer
Center, Boston, MA 02115.
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J Virol, July 1998, p. 6169-6174, Vol. 72, No. 7
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Copyright © 1998, American Society for Microbiology. All rights reserved.
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