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Departments of
* Microbiology and
Pediatrics, University of Iowa, Iowa City, IA 52242
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Immunocompetent mice infected with the neurotropic coronavirus mouse hepatitis virus (MHV), strain JHM, develop acute and chronic demyelinating diseases with clinical and pathological findings similar to those observed in patients with MS (11, 12). By contrast, mice that are immunodeficient, such as recombination activation gene (RAG) knockout mice or SCID mice, do not develop demyelination despite harboring large viral loads (13, 14). Adoptive transfer of T cells from C57BL/6 (B6) mice immunized with MHV to infected RAG 1-/- mice resulted in inflammation, activation of macrophages, and demyelination within 7 days posttransfer (15).
Accumulated evidence from multiple studies indicates that migration of T cells into the inflamed CNS is not Ag specific, and is not dependent on activation status (16, 17, 18, 19). However, T cells that recognize Ags present in the CNS are preferentially retained (16). After splenocytes were transferred from B6 mice to MHV-infected RAG 1-/- mice, a large fraction of CD4 and CD8 T cells present in the CNS recognized MHV-specific epitopes (20, 21, 22). However, T cells with unidentified specificities were also present in the CNS after adoptive transfer, and in immunocompetent mice directly infected with MHV (15, 22). Although some may have been specific for novel CD4 or CD8 T cell epitopes from MHV, others were likely to recognize epitopes not present in MHV or the CNS. The participation of bystander T cells in demyelination has not been investigated. To address this possibility, we infected TCR transgenic/RAG 2-/- mice, which contain monospecific CD8 T cells that do not recognize MHV peptides. The results show that demyelination does occur, but requires specifically activated CD8 T cells. The data highlight a novel mechanism of immune-mediated pathology in the CNS and elucidate an explanation for the observed infection-related exacerbations in diseases such as MS.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(C57BL/6 x C57BL/10SgSnAi)-(transgenic) TCR lymphocytic choriomeningitis virus (LCMV) P14-(knockout) RAG 2 (P14 mice) and B6;129S6-RAG2tml-TgN (N15 mice) mice were purchased from Taconic Farms (Germantown, NY). C57BL/6-RAG 1-/- mice were bred at the University of Iowa.
Virus
The neuroattenuated variant of MHV-JHM, strain J2.2-V-1, was kindly provided by J. Fleming (University of Wisconsin, Madison, WI). In all experiments, mice were infected by intracranial inoculation with 1 x 103 PFU MHV-J2.2-V-1 in 30 µl DMEM plus 15 mM HEPES (pH 7.0). In some experiments, P14 mice were infected with 1 x 105 PFU Armstrong strain of LCMV i.p., generously provided by J. Harty (University of Iowa).
Peptide injections
Three days before infection with MHV, some mice received one i.p. injection of 100 µg peptide emulsified in CFA (Sigma-Aldrich, St. Louis, MO). Peptides used were LCMV gp33 (KAVYNFATM) (provided by M. Buchmeier, The Scripps Research Institute, La Jolla, CA) or vesicular stomatitis virus nucleocapsid protein 52–59 (N52) (RGYVYQGL) (Biosynthesis, Lewisville, TX).
RNase protection assays (RPAs)
RNA was isolated using Tri Reagent, according to the
specifications of the manufacturer (Molecular Research Center,
Cincinnati, OH). RPAs were performed, as previously described
(23), using the probes indicated in Fig. 1
(provided by I.
Campbell, The Scripps Research Institute). Templates for the probes
were linearized with EcoRI and
32P-labeled antisense RNA probes synthesized
using T7 RNA polymerase. We used 5 µg spinal cord RNA for each
hybridization reaction. A probe for L32 was included in each assay as
an internal control. After hybridization and digestion with RNase,
samples were analyzed on denaturing polyacrylamide gels. Gels were then
exposed to a phosphor imaging screen.
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Spinal cords were harvested, fixed in zinc Formalin, and embedded in paraffin. For myelin examination, 8-µm sections were stained with luxol fast blue and counterstained with H&E.
Immunohistochemistry
Spinal cord sections were deparaffinized, rehydrated, and
permeabilized with 0.1% Triton X-100 before blocking with CAS
block (Zymed Laboratories, San Francisco, CA). Following blocking,
sections were incubated with rat anti-mouse F4/80 Ab (Cl A3:1;
Serotec, Oxford, U.K.) or rat anti-TNF-
(clone MP6-XT22; BD
PharMingen, San Diego, CA), washed, and incubated with biotinylated
goat anti-rat Ab (Vector Laboratories, Burlingame, CA). After
incubation with streptavidin-HRP (Jackson ImmunoResearch Laboratories,
West Grove, PA), Ag was detected using 3,3'-diaminobenzidine
(Sigma-Aldrich). Sections were counterstained with hematoxylin.
Imaging
Images of spinal cords were digitized using an Optronics camera attached to a Leitz diaplan light microscope. Demyelination was quantified, as described previously, using Vtrace software (Image Analysis Facility, University of Iowa) (24).
FACS analysis
Lymphocytes were prepared from brains, as previously described
(20). For intracellular staining, lymphocytes were
incubated with EL-4 cells, which served as APCs, and 1 µM peptide in
the presence of monensin (Golgistop; BD PharMingen) for 4–5 h at
37°C. Samples were washed and incubated in blocking buffer
(anti-mouse CD16/CD32 Ab (24G.2) in 10% rat serum). Cells were
stained with FITC-conjugated anti-mouse CD8 (Ly-2), and, in some
samples, PE-conjugated anti-mouse CD44 (IM7) or PE-conjugated rat
Ig (all purchased from BD PharMingen). To detect intracellular IFN-
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cells were washed, fixed, permeabilized, and resuspended in
PE-conjugated anti-mouse IFN- (XMG1.2; BD PharMingen) or
PE-conjugated rat Ig. After incubation and washing, cells were analyzed
using a FACScan flow cytometer (BD Biosciences, San Jose, CA). The
number of lymphocytes harvested from each brain ranged between 2
x 105 and 8.4 x 105.
CNS-derived lymphocytes from individual animals were analyzed in these
experiments.
Quantification of Ag-specific lymphocytes
Numbers of gp33- or N52-specific lymphocytes were calculated as
follows: total number of CNS-derived lymphocytes x the percentage
of CD8 T cells x (the percentage of peptide-specific T cells
- the percentage of cells that expressed IFN- in response to
irrelevant peptide).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MHV-induced inflammatory cytokines and chemokines are likely to be
critical for the rapid recruitment of Ag-specific T cells and
macrophages/microglia into the CNS, and likewise may be important in
recruitment of bystander T cells. In initial experiments, we analyzed
the expression of proinflammatory cytokines and chemokines in the CNS
of 10-day MHV-infected, or uninfected RAG 1-/-
mice by RPA. mRNA for lymphotoxin , TNF-, IL-12 p40, IL-6, and
IL-1
, but not IL-4, was detected in the MHV-infected RAG
1-/- CNS (Fig. 1
A). We detected low levels of
mRNA for lymphotoxin and TNF- in the CNS of naive RAG
1-/- mice (Fig. 1A), in agreement
with previous reports (25, 26). Infection with MHV
resulted in up-regulation of several chemokines, including
CCL2/macrophage chemoattractant protein-1 (MCP-1), CCL7/MCP-3,
macrophage-inflammatory protein-2 (MIP-2), CXCL10/IFN--inducible
protein-10 (IP-10), CCL4/MIP-1, and CCL5/RANTES (Fig. 1B). This profile is identical with the profile of
chemokines expressed in the CNS of immunocompetent C57BL/6 (B6) mice
after MHV infection (27). Astrocytes are the source for
cytokines such as TNF- and IL-1, and chemokines such as
CXCL10/IP-10, in B6 mice chronically infected with MHV (27, 28). Similarly, astrocytes were also the source for a
representative cytokine, TNF-, in MHV-infected RAG
1-/- mice (Fig. 1C). These results
show that a proinflammatory milieu existed in the CNS of MHV-infected
RAG 1-/- mice in the absence of
demyelination.
Non-MHV-specific CD8 T cells caused demyelination if specifically activated before infection
To investigate whether CD8 T cells specific for Ags unrelated to
MHV- or CNS-derived Ags were capable of causing demyelination, we
infected P14 and N15 transgenic mice crossed onto a RAG
2-/- background. The only T cells in these mice
are CD8 T cells specific for residues 33–41 of the LCMV gp33 (P14
mice) or for residues 52–59 of the vesicular stomatitis virus
nucleoprotein (N52) (N15 mice). Both P14 and N15 transgenic mice
infected with MHV were asymptomatic until days 12–14 postinoculation
(p.i.), at which time they developed signs of severe encephalitis
(ruffled fur, hunched posture, lethargy) and rapidly became moribund.
This disease course was identical with that observed in infected
nontransgenic RAG 1-/- mice (13).
As a control for the experiments described below, uninfected mice were
treated with LCMV gp33 emulsified in CFA (CFA:peptide gp33). After this
treatment, mice remained asymptomatic throughout the experiment.
Histologically, spinal cords harvested from uninfected peptide
gp33-treated P14 mice and MHV-infected P14 and N15 mice showed little
evidence of demyelination (Fig. 2, A and C, and data not shown) or macrophage
infiltration (Fig. 2, B and D, and data not
shown). The amount of demyelination in MHV-infected P14 or N15 mice
ranged from 0.41 to 1.77% and was not greater than that observed in
nontransgenic, infected RAG 1-/- mice
(13) (Fig. 3 and Table I).
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E). Colocalized with
these areas of demyelination were numerous activated
F4/80+ macrophages/microglia (Fig. 2F). Quantification of demyelination in peptide-treated,
infected P14 and N15 mice yielded averages of 10.4% (range
5.0–16.5%) and 6.7% (range 4.6–10.5%) for each group, respectively
(Fig. 3 and Table I). When we treated P14 transgenic mice with CFA
alone, or immunized P14 transgenic mice with CFA:peptide N52 3 days
before infection with MHV, we observed no significant demyelination
indicating that the ability of non-MHV-specific T cells to mediate
demyelination was dependent on peptide-specific activation (Table I).
For comparison, MHV-infected RAG 1-/- mice that
received adoptive transfer of MHV-immune CD8 T cell-enriched
populations exhibited 25% demyelination at this same time p.i. (day
14 p.i.) (15).
We activated P14 transgenic T cells in an alternative way to explore
further the relationship between T cell activation and the ability to
cause bystander pathology. We infected P14 transgenic mice i.p. with
the Armstrong strain of LCMV, followed 6 or 8 days later by
intracranial infection with MHV. Demyelination was observed in these
dually infected mice; however, it was not as consistent as the
demyelination that occurred after CFA:peptide gp33 treatment. The range
of demyelination values was 1.9–18.2% with an average of 5.8% (Fig. 3 and Table I). One explanation for this finding is that LCMV infection
is almost cleared from the P14 mice at the time of MHV infection (data
not shown), and T cells are consequently in the contraction phase
(29).
To address the possibility that uptake of CFA:peptide gp33 by APCs and subsequent transport to the CNS contributed to the development of demyelination, adoptive transfer experiments were performed. Initially, splenocytes were harvested from P14 transgenic mice 3 days after treatment with CFA:peptide gp33 or from mice 8 days after infection with LCMV. A total of 5–10 x 106 splenocytes was transferred into RAG 1-/- mice on the same day that they were infected with MHV. Both sets of recipient mice inconsistently developed demyelination (CFA:peptide gp33, range 0.6–7.0%, average 2.6 ± 1.1%; LCMV infected, range 1.2–4.8%, average 2.7 ± 0.6%) (data not shown), presumably due to the extended time that the transgenic T cells were separated from cognate Ag.
To minimize the time that transgenic T cells were separated from cognate Ag, splenocytes were harvested from P14 mice 4 days after treatment with CFA:peptide gp33 and transferred into RAG 1-/- mice, which had been infected with MHV 9 days earlier. These mice consistently developed demyelination by the time they were harvested at day 15 p.i./day 6 posttransfer (average 4.7 ± 0.9%, p < 0.0001 compared with nontransgenic RAG 1-/- mice infected with MHV) (data not shown). This result indicated that recently activated bystander CD8 T cells were capable of causing bystander demyelination even when removed from cognate Ag. This experiment also showed that CFA:peptide gp33 did not directly contribute to demyelination in MHV-infected transgenic mice. In support of this conclusion, demyelination was not detected in MHV-infected CD4 TCR transgenic mice (TCLi/RAG 1-/-) (30) that were treated with CFA:cognate peptide (manuscript in preparation). If CNS entry of CFA:peptide-containing APCs contributed to demyelination, these mice should have developed demyelination because MHV-specific CD4 T cells are efficient mediators of demyelination in infected RAG 1-/- mice (15).
Increased number of activated T cells in the CNS of mice with demyelination
To begin to investigate the relationship between T cell activation
and subsequent steps in the pathological process, we determined whether
there was an increased number of activated transgenic T cells in the
CNS during times when demyelination was observed. Very few P14
transgenic T cells trafficked to the CNS after MHV infection only (Fig. 4 and Table I), and these cells expressed
a variable level of CD44 (Fig. 4B). However, they were not
functionally activated based on the lack of IFN- production after
cognate peptide stimulation (Fig. 4, F and J). We
also detected few P14 transgenic T cells in the CNS after CFA:peptide
gp33 treatment without subsequent infection with MHV (Fig. 4, A, E, and I, and Table I) or after
infection of mice treated with CFA:peptide N52 or CFA alone (Table I).
In striking contrast, prior immunization with CFA:peptide gp33 resulted
in a significant increase in the number of activated P14 transgenic T
cells in the MHV-infected CNS (Fig. 4, C, G, and
K, and Table I). These cells were >95%
CD44+ (Fig. 4C), and approximately
70% made IFN- when stimulated with peptide gp33 (Fig. 4, G and K). Similar results were obtained when we
analyzed the CNS of MHV-infected N15 transgenic mice for activated T
cells (Table I). Together, these results show a correlation between
increased numbers of activated T cells in the CNS at the time of peak
disease and the occurrence of significant demyelination.
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It has previously been shown that areas of demyelination are associated
with increased numbers of activated macrophages/microglia
(13). Consistent with the disease phenotype observed in
infected, CFA:peptide gp33-treated P14 transgenic mice and the data
presented in Fig. 1, macrophage infiltration into the spinal cords of
these mice was significantly increased compared with untreated P14 mice
infected with MHV. To quantify these results, we counted all of the
F4/80+ cells in 1.25-mm-wide cross sections at
eight different levels within spinal cords from three mice in each
group. Significantly more macrophages/microglia were present in
MHV-infected CFA:peptide gp33-treated mice when compared with infected
mice not treated with peptide (119 ± 12 in the infected,
CFA:peptide gp33-treated group vs 15 ± 2 in the MHV-only group,
p < 0.0001). This difference was entirely due to
increased numbers of cells in the white matter. MHV-infected,
CFA:peptide gp33-treated P14 transgenic mice had on average 113 ±
11 macrophages/microglia in the white matter per cross sectional area
compared with 2 ± 1 in the white matter of MHV-infected P14
transgenic mice (p < 0.0001). Low numbers of
macrophages/microglia were detected in the gray matter of both groups
(5 ± 1 for the peptide-treated MHV-infected group compared with
13 ± 2 for the virus only group, p < 0.002).
To investigate whether the observed increased numbers of
macrophages/microglia in the spinal cords of infected, CFA:peptide
gp33-treated P14 transgenic mice correlated with increased expression
of macrophagetropic and other chemokines, we performed RPA on spinal
cord RNA isolated from P14 transgenic mice infected with MHV and from
infected, CFA:peptide gp33-treated mice. mRNAs for lymphotoxin,
CCL5/RANTES, CCL4/MIP-1, CCL3/MIP-1, MIP-2, CXCL10/IP-10, and
CCL2/MCP-1 were assayed in these experiments. Levels of all of these
chemokines were nearly the same in both groups (data not shown). Thus,
these assays did not implicate any specific chemokine in bystander
demyelination.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Cells that were not activated with cognate
Ag, such as those exposed to adjuvant only or to an irrelevant peptide,
were unable to reproducibly induce demyelination.
A likely key component of the demyelinating process observed in
MHV-infected RAG 1-/- mice was the presence of
an inflamed CNS. Viral infection induced the expression of
proinflammatory cytokines and chemokines that are chemoattractants for
T cells and for macrophages (Fig. 1). CCL5/RANTES, CXCL9/monokine
induced by IFN-, and CXCL10/IP-10 are all critical for induction of
the inflammatory response or demyelination in mice infected with MHV
(31, 32, 33). Similarly, in MS patients experiencing relapses,
the CNS is in a state of chronic inflammation, characterized by
elevated levels of proinflammatory cytokines and chemokines such as
TNF-, IFN-, CXCL10/IP-10, CXCL9/monokine induced by IFN-, and
CCL5/RANTES (34, 35). In addition, analysis of brain
tissue from MS patients revealed the presence of lymphocytes expressing
CXCR3, a CXCL9/CXCL10 receptor, and CCR5, a CCL5 receptor, in active
lesions (35).
There is precedence for bystander T cells causing pathology in other
disease models, most notably in mice with herpes stromal keratitis
(36). In these studies, CD4 T cells specific for OVA were
demonstrated to traffic to the eye after corneal infection with HSV-1
and were able to cause lesions in the absence of any HSV-specific CD4
or CD8 T cells. Lesions were more severe if CD4 T cells were activated
before infection. Our study showed that nonvirus-specific CD8 T cells
were also able to cause bystander pathology in the CNS, but unlike the
above-mentioned experiments, we showed that it was a prerequisite that
the CD8 T cells be recently activated. Furthermore, we showed that the
transgenic cells could be activated by infection with LCMV (Table I).
Both of these features mimic the pathological process in MS patients
who develop an infection.
Our results are unlikely to result from cross-reactivity between the transgenic T cells and MHV or CNS Ags for several reasons. First, we observed that both N15 and P14 transgenic T cells caused demyelination, even though they recognize unrelated peptide sequences. Second, we detected no potentially cross-reactive sequences between MHV and peptides gp33 and N52 by computer-based sequence comparisons. Third, infection with MHV in the absence of CFA:peptide treatment did not cause demyelination, consistent with a lack of cross-reactivity between MHV and peptides gp33 or N52. Fourth, it was possible that MHV infection exposed previously hidden CNS epitopes that cross-reacted with epitopes gp33 and N52. However, this is unlikely because MHV infection, without concomitant CFA:peptide treatment, did not result in demyelination, even though these putative CNS epitopes should be exposed and available to activate transgenic T cells under these conditions.
The mechanism of bystander demyelination remains to be determined.
Direct cytolysis is very unlikely given the absence of specific epitope
presentation in the CNS. In contrast, IFN- is critical for
experimental autoimmune encephalomyelitis mediated by CD8 T
cells (37) or CD8 T cell-mediated demyelination in
MHV-infected mice (38). Of note, IFN- is rapidly
down-regulated when T cells are removed from Ag (39).
Consequently, activated P14 or N15 CD8 T cells should no longer express
IFN- by the time that they traffic to the CNS. Thus, it is
unlikely that direct effects of IFN- on MHV-infected cells would be
the primary mechanism of bystander pathology. However, IFN- has an
important role in the induction of chemokines (40), and
tight Ag-specific regulation of chemokine expression has not been
demonstrated. Thus, highly activated CD8 T cells, including the
peptide-activated transgenic T cells in our study, or T cells
responding to an unrelated infection in patients with MS, may secrete
chemokines for a short time after Ag contact is broken. We were unable
to identify a macrophagetropic chemokine that was up-regulated in
CFA:peptide gp33-treated mice. These results are similar to those
obtained after transfer of splenocytes from MHV-immune B6 to
MHV-infected RAG 1-/- mice. In these
experiments, extensive demyelination is observed by 7 days posttransfer
(13, 15); however, even in these mice, levels of
CCL2/MCP-1, CCL7/MCP-3, CCL3/MIP-1, and CCL4/MIP-1 were not
significantly changed compared with mice not receiving transferred
cells. A chemokine that did increase was RANTES (data not shown). This
was consistent with the large increase in lymphocytes observed in the
CNS of recipients of MHV-immune splenocytes because RANTES is largely
produced by T cells. No differences in the levels of RANTES were
observed in the present experiments examining bystander T cells,
probably because there was only a modest increase in the number of T
cells after treatment with CFA:peptide gp33 (Table I). However, it is
still possible that expression of a critical chemokine by activated
gp33-specific CD8 T cells causes localized changes in the spinal cord,
resulting in focal areas of demyelination.
These studies provide one explanation for the observed link between illnesses and relapses in MS patients and other diseases with an autoimmune component. Further studies into the mechanism of demyelination caused by bystander T cells will elucidate new treatments for these patients beyond limiting exposure to microbial agents.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Stanley Perlman, Department of Pediatrics, University of Iowa, Medical Laboratories 2042, Iowa City, IA 52242. E-mail address: Stanley-Perlman{at}uiowa.edu
3 Abbreviations used in this paper: MS, multiple sclerosis; IP-10, IFN--inducible protein 10; LCMV, lymphocytic choriomeningitis virus; MCP, macrophage chemoattractant protein; MHV, mouse hepatitis virus; MIP, macrophage-inflammatory protein; p.i., postinoculation; RAG, recombination activation gene; RPA, RNase protection assay.
Received for publication January 25, 2002. Accepted for publication May 20, 2002.
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References |
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-cell destruction. Diabetes 41:998.[Abstract]
- and -chemokine expression in the central nervous system during mouse hepatitis virus-induced demyelinating disease. J. Immunol. 160:970.) is important in T lymphocyte recruitment and host defense following viral infection of the central nervous system. J. Immunol. 166:1790. dependent in mice infected with a neurotropic coronavirus. J. Immunol. 168:1547.This article has been cited by other articles:
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