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Department of Microbiology-Immunology and Institute for Neuroscience, Northwestern University Medical School, Chicago, IL 60611
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mechanism of TMEV-induced demyelination (TMEV-IDD) is not yet clearly understood. However, recent immunological studies with susceptible SJL/J mice indicate that virus-specific CD4+ T cells with the Th1 phenotype are involved in the pathogenesis of demyelination (6, 7, 8). T cells generated during the course of demyelinating disease primarily recognize three predominant (VP1233–250, VP274–86, and VP324–37) viral epitopes (6, 7, 9). T cell populations specific for the VP1 and VP2 epitopes, infiltrating the demyelinating lesion (7) and present in the periphery (8), are primarily the Th1 type. In addition, prestimulation of T cells specific for these epitopes (but not VP3) results in acceleration of the demyelinating disease, indicating that such T cells are likely involved in the pathogenesis of demyelination (8).
The TCR repertoires involved in autoimmune diseases have extensively been investigated to understand the pathogenic mechanisms. Such information may provide a means to selectively control unwanted T cell responses via TCR-based elimination (10, 11). However, most of the autoimmune models involve repeated immunizations with either peptides or myelin Ags in potent adjuvants. The CNS-infiltrating T cell populations in these model systems range from extreme heterogeneity to some degree of oligoclonal expansions (12, 13, 14, 15). Consequently, it has been difficult to interpret whether local expansion of T cells are important for the pathogenesis in these autoimmune models. In contrast, Theiler’s virus-induced demyelination does not require repeated immunizations with adjuvants; a single intracerebral inoculation of a small number (as low as 104 PFU) of live virus consistently induces Th1-mediated demyelinating disease (16). The CTL response is considered to be the most important defense against viral infection, and consequently, the majority of studies in viral infections have focused on the CTL repertoire and function. Systemic as well as local expansion of virus-specific CD8+ cytotoxic T cells in infected mice has been observed in many different virus systems (17, 18, 19, 20, 21, 22, 23, 24). Despite the clonal expansions of CTL specific for viral epitopes after viral infection, the TCR repertoire of these T cells range from extreme heterogeneity to marked skewing in the Vß usage as well as CDR3 sequences. However, very few studies have been reported on such an expansion of virus-specific CD4+ T cells during the development of virus-induced, immune-mediated inflammatory diseases. Thus, investigation of the T cell repertoire in the CNS during the initiation and progression of demyelinating disease induced after viral infection may reveal important immune mechanisms involved in the Th1-mediated pathogenesis.
Previously, we have investigated the nature of peripheral T cell response to one of the major pathogenic Th1 epitopes (VP1233–250 region) and found it to be extremely heterogeneous in the fine minimal epitope regions and in the CDR3 sequences, although one particular Vß was preferred (25). However, conflicting results were reported regarding the predominance in the Vß usage and clonal restriction of infiltrating T cells in the demyelinating lesions (26, 27, 28). In this study, we have analyzed the diversity of the TCR ß-chain of T lymphocytes infiltrating the CNS of virus-infected mice at early and late stages, using PCR-based spectratyping and sequencing of the CDR3 region. Our results clearly demonstrate that T cells are clonally expanded in the CNS as early as 7 days after viral infection and remain in the CNS throughout the course of demyelination. However, such clonal expansion was not detectable in the CNS of mice with proteolipid protein (PLP) peptide-induced experimental autoimmune encephalomyelitis (EAE). Several of these expansions apparently represent T cells specific for known viral epitopes. The initial T cell repertoire seems to be more diverse than that observed in the later stage of viral infection, suggesting continuous Ag stimulation and specific clonal expansion in the CNS in these mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female (4–6 wk old) SJL/J mice were purchased from Charles River Laboratory (Wilmington, MA). Mice were subsequently housed in the animal care facility at Northwestern University (Chicago, IL).
Viruses
A BeAn 8386 virus stock was propagated in BHK-21 cells in DMEM supplemented with 7.5% donor calf serum.
Infection of mice with TMEV
SJL/J mice were infected intracerebrally with 2 x 106 PFU of TMEV in 30 µl of DMEM. The mice were sacrificed at various time intervals after viral infection. Spleens were removed first, and then spinal cords were dissected after extensive perfusion with cold PBS to prevent contamination with circulating lymphocytes.
Induction of EAE by immunization with PLP139–151
Mice were immunized with PLP139–151 in a modified CFA as previously described (29). Each mouse received 100 µl of CFA emulsion containing 200 µg of Mycobacterium tuberculosis H37Ra (Difco Laboratories, Detroit, MI) and 87 µg of PLP139–151 s.c. over three areas on the flank. Mice were scored according to their clinical severity as previously described (30): grade 0, no abnormality; grade 1, limp tail; grade 2, limp tail and hind limb weakness; grade 3, partial hind limb paralysis; and grade 4, complete hind limb paralysis. Initial clinical signs of disease were observed at day 13 after immunization with PLP139–151. At 18 days after immunization, mice with clinical scores between 3 and 4 were used for spectratyping of infiltrating T cells in the CNS after perfusion.
cDNA synthesis and PCR amplification
Total RNA was extracted from spleens or spinal cords using
guanidine isothiocyanate (31) and cDNA synthesized by
reverse transcription. The relative concentrations of cDNA were
estimated based on the level of ß-actin amplification (35 cycles) by
PCR. Each Vß was assessed using a sense sequence primer of the
individual Vßs (Vß1, -2, -3, -4, -5, -6, -7, -10, -14, -15, -16,
-17, -18, and -19) and a common antisense primer of downstream Cß as
listed in Table I
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CDR3 size spectratyping was performed as described previously
(32, 33) with minor modifications. cDNA was amplified with
Vß-Cß primer pairs (Table I
), and 1 µl of primary PCR product was
then subjected to 30 cycles of a secondary amplification with the same
Vß primers and a 32P-end-labeled upstream Cß
primer for Vß-Cß spectratyping or
32P-end-labeled Vß primer and individual Jß
primers for Vß-Jß spectratyping. Although the Jß primer sequences
were identical with those published previously (33), the
PCR condition was modified to reduce cross-amplification with different
Jß primers (60°C for annealing in the presence of 30 mM
(NH4)2SO4).
Radioactive PCR products were mixed with equal volumes of denaturing
buffer and heated at 94°C for 5 min. Three microliters of the samples
were loaded onto a 6% acrylamide sequencing gel and were analyzed
after exposure to Kodak (Rochester, NY) X-OMAT LS film.
Sequencing of PCR products
DNA isolated from individual bands on the acrylamide gel was further amplified (35 cycles) with appropriate primer pairs. The resulting PCR products were cloned into pGEM-T vector (Promega, Madison, WI) and then sequenced by the dideoxynucleotide termination method using the Sequenase kit (USB, Cleveland, OH). The CDR3 size has been defined as the number of residues minus four between the aligned cysteine (C) in the Vß element and the GXG triplet in the Jß region (34). Thus, Vß-CAS S-QERGS-SYEQYFGPG-Jß is counted as 10 amino acid residues.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The relative usage of Vß subfamilies by infiltrating T cells in
the CNS was initially analyzed at various time points after
intracerebral inoculation with Theiler’s virus. The Vßs (Vß8, -9,
-11, -12, and -13) that are deleted in the genome of the SJL/J mouse
were excluded from assessment. The Vß5, also not present in
SJL/J, was included as a negative control. The relative levels of
Vß usage by the infiltrating T cells during the course of
demyelinating disease were analyzed by agarose gel electrophoresis
(Fig. 1). Four time points after
virus infection were selected: 7 days for an early stage, 24 days
for just before onset of disease, 35 days for the beginning of
onset of clinical signs, and 55 days for a middle-late stage of
disease. Infiltration of T cells in the spinal cords could be
detected as early as 7 days after viral infection and continued at 24,
35, and 55 days postinfection. However, the Vß usage was mainly
restricted to Vß1 and Vß2 at the early stage (7 days postinfection)
of TMEV-IDD, and this became more diversified as the disease
progressed. This diversity in Vß usage increased gradually and peaked
at 35 days after viral infection. The restricted Vß usage during
early infection was detectable only in the spinal cords, and all the
Vßs except the negative control were similarly detected in the spleen
from either virus-infected or -uninfected mice. The lack of Vß
amplifications was apparent in the spinal cord of mice mock-infected
with media, indicating that such an infiltration of T cells in the CNS
is dependent on viral infection (Fig. 1). These results strongly
suggest that T cells with a restricted Vß usage appearance initially
in the CNS after TMEV infection before the accumulation of T cells with
expanded Vß repertoire, as the pathogenesis of demyelination
progresses.
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Because infiltrating T cells at the early stage of viral infection
utilize primarily Vß1 and Vß2 (Fig. 1), T cells with these Vßs
were further investigated. The level of CDR3 diversity among
infiltrating T cells expressing Vß1 or Vß2 was initially analyzed
by sequencing the Vß-Cß cDNA clones that were derived from RT-PCR
of spinal cords at an early (day 9) and a late stage (day 65).
Table II shows the CDR3 sequences of
TCR ß-chain bearing Vß1 and Vß2 subfamilies. Some CDR3 sequences
were repeatedly found, e.g., 5 of the 25 Vß1-Cß clones displayed
QERGS-SYEQYF(Jß2.6), and 11 of 22 Vß2-Cß clones exhibited
AGD-YAEQFF(Jß2.1). These results strongly suggest the clonal
expansion of such Vß1+ and
Vß2+ T cell populations in the spinal cords of
virus-infected mice. However, the relative frequencies of the CDR3
sequences found at early and late stages appear to be somewhat
different. For example, the Vß1-QDTE-YEQYF(Jß2.6) sequence (4 of 12
clones) and the Vß2-AGGGG/A-YEQYF(Jß2.6) sequence (7 of 12 clones)
were the most frequent at day 65, whereas these were either minor (1 of
25) or much less frequent (4 of 22) at day 9 postinfection,
respectively. These results indicate that some T cell clones from the
initial infiltration are further expanded, whereas certain T cell
clones contracted as the demyelination progressed. Nevertheless, most
of the predominant CDR3 sequences detected at the early stage of
infection were maintained during the course of viral infection, in that
the same sequences are also found at a late stage (65 days
postinfection).
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The size distribution of the CDR3 regions of selective Vß-Cß
and Vß-Jß combinations of T cells from the spleens and spinal cords
of virus-infected mice were compared (Fig. 2A). The CDR3 spectratypes of
the spleens from uninfected mice showed a Gaussian distribution,
indicating a typical heterogeneous distribution of CDR3 sizes among the
T cells in the periphery. The pattern of CDR3 size distribution of
splenic T cells from infected mice (Fig. 2A) was identical
with that of uninfected mice (Fig. 2B), suggesting that the
presence of virus-induced T cells in the periphery does not alter the
pattern of normal CDR3 size distribution. In contrast, the CDR3
spectrum of the T cells from the pooled spinal cords of infected mice
was markedly skewed. Vß-Cß as well as Vß-Jß combinations
displayed one or two predominant bands, suggesting the expansion of
specific T cell clones. All major bands from spinal cords at 9 days
postinfection, except the 10-aa size band detected in the Vß2-Jß2.6
combination, were apparently maintained throughout the course of
demyelinating disease, as readily seen in the pooled spinal cords at 65
days postinfection. However, several bands reflecting newly expanded T
cell clones (e.g., 9 aa in Vß2-Cß, 8 aa in Vß1-Jß2.6, and 9 aa
in Vß2-Jß2.6) were detected only in the spinal cords at the late
stage (65 days) of viral infection. The initial Vß1-Jß1.1 and
Vß1-Jß2.1 spectratyping yielded one prominent band each (Fig. 2A). However, assessment of the CDR3 sequences revealed that
the Jß1.1 had been cross-amplified by Jß1.3 primer and that the
Jß2.1 had been cross-amplified by Jß2.6 primer in these particular
combinations (data not shown). The PCR condition was further optimized
by addition of
(NH4)2SO4
to prevent the cross-amplification in subsequent studies (see
Materials and Methods for details).
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B). The spectratypes of the splenic T cells from this
virus-infected mouse again showed the Gaussian distribution in each
combination, representing a typical heterogeneous CDR3 pattern of bulk
T cells. The faint bands in the Vß1-Jß1.5 and Vß2-Jß1.5
spectratypes may reflect the rare use of Jß1.5 in SJL/J mice
(35). Perhaps this is because of the polymorphism in this
mouse strain at the very beginning of this Jß (36). In
contrast to the heterogeneous pattern of splenic T cells, only a few
prominent bands were observed in the combinations of Vß1-Jßs and
Vß2-Jßs of the infiltrating T cells, suggesting a marked expansion
of restricted T cell clones. The pattern was very similar to that seen
with the pooled spinal cords (Fig. 2A), although some
differences in the band pattern were noted. These differences may
represent minor variations in the repertoire development of
infiltrating T cells in response to viral infection among different
individual mice. Nevertheless, the predominant CDR3 pattern is similar
among individual mice, suggesting an Ag-driven T cell expansion in the
CNS of virus-infected mice. Analyses of CDR3 sequences of the major spectratype bands
To analyze the degree of CDR3 heterogeneity in the individual
major bands of Vß-Cß or Vß-Jß combinations, each band was
excised, cloned, and subsequently sequenced (Table III). Every band displayed highly
homogeneous nucleotide sequences for each, suggesting that the
individual bands in the spectratyping indeed represent clonal
expansions of specific T cells. Because the spectratype pattern of
pooled spinal cords at 9 days postinfection was similar to that at 65
days (Fig. 2), the representative major bands of the Vß-Cß
amplifications were analyzed initially (Table III). The CDR3 sequence
data clearly indicate that the majority of T cell clones initially
expanded at early stage of viral infection remained predominant
throughout the course of demyelinating disease. In addition, it appears
that a restricted number of T cell clones are predominant for these
Vß subfamilies, in that each prominent CDR3 size of the Vß-Cß
combinations contains only one or two identical CDR3 sequences (Table III). The band patterns and sequence data suggest that such T cell
expansions become somewhat more restricted within cells expressing the
same Vßs at a later period. The most frequent CDR3 sequences
corresponded well to the sequences of cDNA clones generated directly
from the spinal cords of virus-infected mice (Table II). These data
clearly indicate that viral infection induces and maintains identical
predominant T cell clones in individual mice during the entire course
of demyelinating disease.
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). The majority of individual
bands represent a single clone of T cells, and the others also contain
very restricted numbers of clones based on the identical or restricted
sequences for each band. Again, the frequency of sequences from the
Vß-Jß spectratype bands matched well with that of Vß-Cß bands
or sequences of Vß-Cß cDNA clones derived directly from spinal
cords. When the sequences of Vß-Jß spectratype bands were compared
between the pooled spinal cords and a single cord, the major
predominant bands of the single cord were identical with the sequences
of the pool. However, minor individual variations in the sequences
(Table III) as well as in the spectratyping pattern (Fig. 2) were
noted, suggesting that different T cell clones may also be expanded in
individual mice in response to the same virus. Presence of CDR3 sequences specific for viral epitopes in the spectratype bands
We previously generated many different Th cell clones and
hybridomas reactive to the viral capsid epitopes, and some of the TCR
CDR3 regions were analyzed (Ref. 25 and unpublished data).
Because VP1233–250- and
VP274–86-specific T cell clones could be derived
from the CNS infiltrates, such T cells are most likely represented in
the inflammatory lesions (7). To verify whether the
clonally expanded T cells in the CNS identified by spectratyping
include virus-specific Th cells, the CDR3 sequences of virus-specific T
cell hybridomas and clones with known epitope specificity were compared
with those found in the spectratype bands. The CDR3 sequences identical
with that of T cell clones/hybridomas specific for
VP274–86 and VP324–37
were found in certain spectratype bands. These include
Vß2-ATD-Jß1.1 specific for VP274–86 (Fig. 2A and Table III) and Vß16-RGRN-Jß1.1 specific for
VP324–37 (data not shown). Therefore, it is most
likely that these clonally expanded T cell populations include
CD4+ Th cells specific for viral epitopes.
However, comparison of the CDR3 sequences of the spectratype bands with
the epitope specificity is difficult due to the extensive diversity of
CDR3 sequences and the limited sequence data for functional T cells
directly derived from the CNS infiltrates.
Comparison of the CDR3 spectratypes to that of infiltrating T cells from mice with EAE
It has previously been reported that T cell clones recognizing the
encephalitogenic PLP epitope (PLP139–151) in
SJL/J mice with EAE, an autoimmune model of human MS, use diverse TCR
repertoire (12, 14). To compare the magnitude of
infiltrating T cell repertoire involved in TMEV-induced demyelination
to that involved in EAE, similar analyses of CDR3 in
PLP139–151-induced EAE were performed (Fig. 3 and Table IV). The CDR3 spectratype patterns of
spinal cord T cells from SJL/J mice with EAE were extremely diverse,
similar to that observed in the spleen. Furthermore, the sequence data
of two representative spectratyping bands unequivocally support the
exceptional TCR heterogeneity of infiltrating T cells in EAE (Table IV). No two cDNA clones showed identical sequences except one duplicate
CDR3 sequence in the Vß1-Jß2.6 combination (Vß1-QVRPGR-Jß2.6).
This extreme diversity of TCR repertoire in EAE sharply contrasts to
that seen in TMEV-IDD (Table III). Therefore, infiltrating autoreactive
T cells involved in the induction of EAE are not likely to represent
clonally expanded T cells in the CNS. This may represent the
differences in the nature of T cell activation in these model systems,
i.e., extensive peripheral stimulation of autoantigen-reactive T cells
in the presence of potent adjuvant vs selective clonal expansion of
virus-induced T cells in the CNS due to the tissue-confined chronic
viral persistence.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study, we have analyzed the TCR Vß repertoire at the clonal
level by spectratyping and sequencing the CDR3 region of infiltrating T
cells after TMEV infection in susceptible SJL/J mice. This approach has
been used successfully to identify oligoclonal T cell expansion without
isolating T cells during viral infections and/or immune-mediated
disease states (15, 20, 21, 22). Dramatic clonal expansion has
recently been observed after lymphocytic choriomeningitis virus
infection (21, 22). However, such drastic clonal expansion
has been less clear in the host infected with other viruses or
undergoing immune-mediated diseases (17, 18, 19, 20). We
demonstrate here that clonally restricted T cells accumulate in the CNS
as early as 7 days after viral infection and that this expansion is
maintained throughout the course of virally induced demyelinating
disease (Fig. 2 and Table III). This is markedly different from the
nature of T cell populations involved in
PLP139–151-induced EAE, where no such clonal
expansion is apparent in the CNS during the autoantigen-induced
demyelinating disease (Fig. 3 and Table IV). The lack of clonal
restriction of T cells found in EAE does not appear to reflect the
differences in the level of T cell infiltration in that comparable
numbers of T cells have been found in these two different systems (Ref.
28 and data not shown). However, although it is unlikely,
the possibility of similar clonal restriction among T cells bearing
Vßs other than those tested in this study cannot be excluded. In
addition, it is conceivable that Vß bias becomes more pronounced when
whole proteins relying on naturally processed T cell determinants
rather than on peptides are used, as shown in myelin basic
protein-induced EAE in the rat system (43, 45).
Nevertheless, the accumulation of clonally restricted T cells in the
CNS of TMEV-infected mice is much more pronounced and most likely is a
result of the fact that the majority of infiltrating cells in the
demyelinating lesions are void of nonspecific T cell populations found
in the periphery. Therefore, this clonal accumulation in the CNS after
viral infection strongly suggests that such T cells have been locally
stimulated and expanded in response to chronic viral persistence
because no detectable skewing patterns are found in the peripheral T
cells of virus-infected mice.
Using the DA strain of TMEV, Rodriguez (26) reported
previously that no TCR Vß subfamily is preferentially used by
infiltrating T cells in the spinal cords of resistant (B10.K) or
susceptible (B10.Q) mice during the early or late course of viral
infection. In addition, no such preferential use of Vßs by
infiltrating T cells was observed even in highly susceptible SJL mice
at a late (day 45) or very late (day 238) stage (26).
These studies were based on the relative RT-PCR amplifications of
Vß-Cß combinations and were interpreted as the lack of specific
clonal expansion in the infiltration. In contrast to the above studies,
our results clearly indicate that preferential use of certain Vß
subfamilies can be detected at an early stage of viral infection (days
7–9) in susceptible SJL mice, although the Vß usage is expanded as
the infection progresses (Fig. 1). The CDR3 size distribution pattern
of infiltrating T cells in the CNS of SJL/J mice has also been
investigated by another group (27), and this group showed
highly restricted CDR3 sizes in many Vß-Jß combinations of
infiltrating T cells after infection with TMEV DA strain. However,
sequencing results of two representative bands displayed extremely
heterogeneous CDR3 sequences, rendering these results very difficult to
interpret. In sharp contrast to the above studies with the DA strain,
our sequencing results (Table III) of the predominant bands clearly
indicate that skewing in the CDR3 size bands indeed represents clonal
expansion of T cells in the CNS infiltration. The discrepancies between
our current study and the previous studies with TMEV may reflect the
differences in the virus strains used (BeAn vs. DA) and/or the dose of
virus used for infection. Our observation of significantly more
heterogeneous T cell responses after infection with a high dose of
virus or a low-pathogenic variant virus strongly supports these
possibilities (data not shown). Because a viral dose resulting in
clinical demyelinating disease in virtually 100% mice was used in our
study, such clonal expansion of T cells must be involved in the
pathogenesis of virus-induced, immune-mediated demyelinating
disease.
Because some of the CDR3 sequences match with those of virus-specific Th cells selected in vitro, these clonal expansions are most likely to be driven in response to viral infection. This is consistent with the predominant clonal expansion of CD8+ CTL population, in which virus-specific expansion of T cell population is apparent (21, 22). Similarly restricted CDR3 size band distributions and sequences have also been observed in these studies. However, it is not yet clear whether all of the expanded T cell clones represent virus-specific T cells or if they include autoreactive T cells generated because of "epitope spreading" as a result of immune-mediated tissue damage by virus-specific T cells (44). In addition, the contribution of CD8+ T cells in the predominant spectratyping pattern is also not clear, although presence of low levels of CD8+ T cells and CTL function toward TMEV are found in susceptible SJL/J mice (46). It is most likely that the T cell responses to viral infection may include both CD4+ Th as well as CD8+ T cells specific for viral Ags and/or autoantigens generated after viral infection. Nevertheless, our experimental data clearly demonstrate that T cells are clonally expanded in the infiltrating lesions of demyelination throughout the course of disease, although the TCR repertoire appears to be broad. We are currently further analyzing the major T cell population expanded during viral infection to correlate with the pathogenicity and Ag specificity involved in the T cell expansion. These studies may provide useful information on the nature of T cell populations that are involved in the pathogenesis of demyelinating disease.
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Anatomical Pathology, Korea University Medical Center, Seoul, Korea.
3 Address correspondence and reprint request to Dr. Byung S. Kim, Department of Microbiology-Immunology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611.
4 Abbreviations used in this paper: TMEV, Theiler’s murine encephalomyelitis virus; TMEV-IDD, TMEV-induced demyelination; MS, multiple sclerosis; PLP, proteolipid protein; EAE, experimental autoimmune encephalomyelitis.
Received for publication February 14, 2000. Accepted for publication April 19, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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