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Journal of Virology, March 2001, p. 3043-3047, Vol. 75, No. 6
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.6.3043-3047.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
High-Magnitude, Virus-Specific CD4 T-Cell Response
in the Central Nervous System of Coronavirus-Infected Mice
Jodie S.
Haring,1
Lecia L.
Pewe,2 and
Stanley
Perlman1,2,*
Departments of
Microbiology1 and
Pediatrics,2 University of Iowa, Iowa
City, Iowa 52242
Received 12 October 2000/Accepted 16 December 2000
 |
ABSTRACT |
The neurotropic JHM strain of mouse hepatitis virus (MHV) causes
acute encephalitis and chronic demyelinating encephalomyelitis in
rodents. Previous results indicated that CD8 T cells infiltrating the
central nervous system (CNS) were largely antigen specific in both
diseases. Herein we show that by 7 days postinoculation, nearly 30% of
the CD4 T cells in the acutely infected CNS were MHV specific by using
intracellular gamma interferon (IFN-
) staining assays. In mice with
chronic demyelination, 10 to 15% of the CD4 T cells secreted IFN-
in response to MHV-specific peptides. Thus, these results show that
infection of the CNS is characterized by a large influx of CD4 T cells
specific for MHV and that these cells remain functional, as measured by
cytokine secretion, in mice with chronic demyelination.
| |
TEXT |
Recent studies have shown that the
CD8 T-cell response is largely directed at the inciting agent in many
human and experimental infections (1, 3, 7, 14, 17).
However, much less is known about the specificity of CD4 T cells in
these infections. CD4 T cells have a crucial role in the pathological
process in experimental models of demyelination and in the human
disease multiple sclerosis (MS). Mouse hepatitis virus (MHV) strain JHM (MHV-JHM) causes acute and chronic neurological diseases, including demyelinating encephalomyelitis, in susceptible strains of rodents (9, 19). Although demyelination in this model system was initially believed to result from direct viral lysis of
oligodendrocytes, demyelination was demonstrated to be largely immune
mediated in more recent reports (8, 10, 24, 26, 29). Both
the acute encephalitis and chronic demyelinating diseases caused by
MHV-JHM are characterized by extensive infiltration of the central
nervous system (CNS) by mononuclear cells.
As part of the process of assigning a specific role to CD4 T cells in
the induction of either acute or chronic CNS disease, it is critical to
determine the number, kinetics of appearance, and specificity of CD4 T
cells in the CNS. Previously, CD4 T cells recognizing MHV-specific
epitopes were identified by using bulk populations of CNS-derived
lymphocytes in gamma interferon (IFN-) enzyme-linked immunospot
(ELISPOT) assays (30), but conditions were not
optimized for quantification in these experiments. At least three CD4
T-cell epitopes are recognized in the CNS of mice with MHV-induced
neurological disease. These encompass residues 134 to 147 of the
transmembrane (M) protein [epitope M(134-147)] and residues 333 to
347 and 358 to 372 of the surface (S) glycoprotein [epitope
S(333-347) and epitope S(358-372)]. CD4 T cells responding to
epitope M(134-147) are most abundant in the CNS of mice with either
acute encephalitis or chronic demyelination (30). In order
to obtain more precise quantification, intracellular IFN- staining
was used to analyze functionally activated, MHV-specific CD4 T cells in
the CNS of infected mice.
A large fraction of the CD4 T cells infiltrating the CNS is MHV
specific.
Lymphocytes were harvested from the CNS of mice with
acute encephalitis as previously described (4). Typically
0.8 × 106 to 1.0 × 106 lymphocytes were harvested from each brain
and spinal cord by day 7 after intranasal inoculation with MHV.
Lymphocytes were stained for intracellular IFN- production as
previously described (28). In order to quantify accurately
the frequency of virus-specific CD4 T cells in the CNS, we optimized
the intracellular IFN- staining assay. CHB3 cells
(I-Ab), derived from a B-cell tumor
(2), were used to present MHV-derived peptides, because we
detected suboptimal stimulation after in vitro culture with
naïve splenocytes. We determined that a ratio of 5 CHB3 cells
to 1 lymphocyte resulted in optimal stimulation of CD4 T cells in this
short-term in vitro culture.
A small proportion of CD4 T cells expressed IFN- in the absence of
added peptide (Fig. 1D). Although the
basis of this expression is not known, it may result from stimulation
by infected microglia or macrophages present in the CNS cell
preparation (31). To calculate the percentage of
MHV-specific CD4 T cells, the frequency of cells that spontaneously
expressed IFN- was subtracted from the frequency observed after
peptide stimulation. This may underestimate the number of MHV-specific
cells, since it is likely that at least some of the cells that
spontaneously expressed IFN- were MHV specific. By days 6 to 7 postinfection (p.i.), a large infiltrate of CD4 T cells was detectable
(Fig. 1). Approximately 15 to 20% of the CD4 T-cell population was
specific for epitope M(133-147) (Fig. 1A). As expected, these epitope
M(133-147)-specific cells were CD44hi,
indicative of current or past activation (Fig. 1E). An additional 6%
of the CNS-derived CD4 T cells were specific for epitopes S(333-347) and S(358-372) (Fig. 1B and C). These results showed that
approximately 25 to 30% of the CD4 T cells in the acutely infected CNS
were MHV specific. The actual percentage of MHV-specific CD4 T cells may be even higher, since we identified cells recognizing only three
MHV-specific CD4 T-cell epitopes, and it is likely that additional
stimulatory epitopes are present.
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FIG. 1.
Substantial numbers of CD4 T cells specific for
MHV-specific epitopes were detected in the acutely infected CNS.
Six-week-old C57BL/6 mice (National Cancer Institute, Bethesda, Md.)
were inoculated intranasally with MHV-JHM (4 × 104
PFU). Lymphocytes were harvested from the CNS of moribund mice (6 to 7 days p.i.). Cells from four mice with acute encephalitis were pooled
and analyzed for IFN- expression after stimulation with peptide
M(133-147) (A), peptide S(358-372) (B), peptide S(333-347) (C), or
no peptide (D). All of the epitope M(133-147)-specific CD4 T cells in
the acutely infected CNS were CD44hi (E), consistent with
an activated phenotype. No staining was detected if an isotype-matched
phycoerythrin-conjugated control antibody (PharMingen, San
Diego, Calif.) was used in lieu of anti-IFN- antibody (F). Numbers
indicate the percentage of CD4 T cells in each quadrant. This
experiment is representative of 10 individual experiments.
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TCR V
usage by M(133-147)-specific CD4 T cells is extremely
diverse
Studies of MHV-JHM-infected mice as well
as those using other infectious models have shown that the CD8 T-cell
response to dominant epitopes is generally polyclonotypic (6, 12,
17), but little is known about the diversity of epitope-specific
CD4 T-cell responses in viral infections. To determine the diversity of
T-cell receptor (TCR) expression within the epitope
M(133-147)-specific CD4 T-cell population, surface staining for
individual TCR V regions was used in conjunction with intracellular
staining for IFN- followed by fluorescence-activated cell sorter
(FACS) analysis. M(133-147)-specific CD4 T cells expressed a diverse
group of chains with only a small amount of skewing relative to
V usage by CD4 T cells harvested from the naïve spleen (Fig.
2). Previous results showed that the
MHV-specific CD8 T-cell response was polyclonotypic, although it was
characterized by preferential usage of a few V segments
(17). The data in Fig. 2 indicate that V expression by
MHV-specific CD4 T cells was even more diverse than that by virus-specific CD8 T cells.
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FIG. 2.
Comparison of the V phenotypes of epitope
M(133-147)-specific and nonspecific CD4 T cells isolated from the
infected CNS and splenocytes harvested from naïve mice.
Lymphocytes were harvested from the CNS of four to six infected mice 7 days p.i. and pooled. V surface staining, using a previously
described panel of biotinylated monoclonal antimouse V antibodies
(PharMingen) (17), and intracellular staining for IFN-
were done after stimulation with peptide M(133-147). The bars
represent the percentage of CNS-derived peptide M(133-147)-specific,
nonspecific, and splenic CD4 T cells that were also positive for the
indicated V element. Rat Ig is a biotinylated control antibody
(Caltag, Burlingame, Calif.). Values shown for CNS-derived CD4 T cells
are the average of six experiments. Error bars show the standard error
for each value. Values shown for naïve splenic CD4 T cells are
the average of two independent experiments.
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Both MHV-specific CD4 and CD8 T cells infiltrated the CNS at early
times p.i.
Previous results suggest that CD4 T cells are necessary
for the survival of CD8 T cells in the infected CNS (18).
To determine if MHV-specific CD4 T cells were detected prior to CD8 T
cells, the appearance of both types of T cells in the CNS, draining
cervical lymph nodes (CLN), and spleen was monitored. Lymphocytes were purified from mice at 3 to 7 days p.i. MHV-specific CD8 T cells were
detected with intracellular IFN- assays as described previously (28), by using EL-4 cells
(H-2Db, Kb)
to present antigen (ratio of 1 EL-4 cell to 50 lymphocytes). By day
6 p.i., approximately 8% of the total CD4 T cells in the CNS were
M(133-147) specific (1,300 to 1,400 cells). The number of
virus-specific CD4 T cells continued to increase rapidly until mice
were moribund (Fig. 3). By 7 days p.i.,
approximately 15% of the CD4 T cells in the CNS were M(133-147)
specific, equivalent to an absolute number of 11,000 cells per infected
brain. Cells responding to the subdominant CD4 T-cell epitopes
S(333-347) and S(358-372) accumulated with nearly the same kinetics
shown for epitope M(133-147), but exhibited proportionately lower
frequencies and absolute cell numbers (Fig. 3).
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FIG. 3.
Kinetics of appearance of MHV-specific CD4 and CD8 T
cells in the CNS. Intracellular staining for IFN- was done on
lymphocytes isolated from the brains of mice on days 3 to 7 p.i.
The percentage of MHV-specific T cells was calculated by subtracting
the percentage of lymphocytes that express IFN- spontaneously (CD4 T
cells) or in response to irrelevant peptide (CD8 T cells) from the
percentage of lymphocytes that expressed IFN- when stimulated with
an MHV-specific peptide. The absolute number of MHV-specific T cells
per mouse was calculated as follows: total number of CNS-derived
lymphocytes × the percentage of CD4 or CD8 T cells × (the
percentage of MHV-specific T cells  the percentage of cells that
express IFN- spontaneously or in response to irrelevant peptide).
The percentage (A) and absolute number (B) of MHV-specific T cells are
shown. Values shown are averages of three to five experiments. Error
bars show the standard error for each value.
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|
The appearance of CD8 T cells in the CNS paralleled that of CD4 T
cells. By day 6 p.i., approximately 15% of the CD8 T cells
(3,000 to 4,000 cells) were specific for epitopes S(510-518) and
S(598-605).
A vast expansion of antigen-specific CD8 T cells occurred
between 6 and
7 days p.i., similar to the expansion observed in
the CD4 T-cell
population (Fig.
3). By day 7 p.i., 50% of the
total CD8 T cells
were S(510-518) or S(598-605) specific. The
expansion of CD8 T cells
from day 6 to day 7 p.i. was greater
than that of CD4 T cells, but
the resulting number of epitope
S(510-518)-specific CD8 T cells was
only two- to threefold greater
than the number of M(133-147)-specific
CD4 T cells at day 7 p.i.
These results indicated that the
MHV-specific CD4 and CD8 T-cell
responses were both robust in the
infected
CNS.
In contrast, MHV-specific CD4 T cells were detected in the CLN only at
low frequency. Initially, we could not detect any MHV-specific
CD4 T
cells in the CLN at any time p.i. However
, by first
selecting CD4 T cells with an activated phenotype
(CD44
hi or CD62L
lo), low
numbers of MHV-specific CD4 T cells were detectable in
the CLN. They
were detected simultaneously with, or just prior
to, their appearance
in the CNS, and the number continued to increase
over the course of the
infection in parallel with the rapid expansion
observed in the CNS.
MHV-specific CD4 T cells were present in
the spleen only at very low
frequencies (<1.0%), even after selection
for activated cells (data
not
shown).
A reduced fraction of CD4 T cells in the chronically infected CNS
was MHV specific.
Suckling mice inoculated intranasally with MHV
develop a fatal encephalitis unless they are nursed by dams previously
immunized with live MHV. Under these conditions, 40 to 90% of mice
develop clinical signs of hindlimb paralysis and histological evidence of demyelination at 3 to 8 weeks p.i. with high titers of infectious virus present in the CNS of these animals (16). CD4 T
cells have an important role in the development of MHV-induced
demyelination (11, 28), but in other virus infections, CD4
T cells become unresponsive during the course of persistence
(15). Next, we determined the state of responsiveness of
MHV-specific CD4 T cells in the chronically infected CNS as measured by
IFN- expression (Fig. 4). Data from
analyses of five individual mice with chronic demyelination (harvested
24 to 36 days p.i.) showed that 7.8% (± 1.5%), 1.5% (± 0.5%), and
2.1% (± 0.8%) responded to peptides M(133-147), S(333-347), and
S(358-372), respectively. These percentages were lower than what was
detected in mice with acute encephalitis (Fig. 1). Whether this
represents an actual decrease in number of cells responding to the
three MHV-specific epitopes or a decreased ability to produce IFN-
remains to be determined. The decrease in number of CD4 T cells making
IFN- is not due to a cytokine profile switch to a Th2 phenotype,
since no M(133-147)-specific CD4 T cells stained positive for IL-4
after peptide stimulation (data not shown). All of the epitope
M(133-147)-specific CD4 T cells in the chronically infected CNS are
CD44hi (Fig. 4E).
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FIG. 4.
MHV-specific CD4 T cells were detected in the CNS of
mice with chronic demyelination. Lymphocytes were harvested from the
brain and spinal cord of a mouse with hindlimb paralysis at day 36 p.i. Intracellular staining for IFN- was done after stimulation with
peptide M(133-147) (A), peptide S(358-372) (B), peptide S(333-347)
(C), or no peptide (D). Numbers indicate the percentage of CD4 T cells
in each quadrant. All of the epitope M(133-147)-specific CD4 T cells
in the chronically infected CNS were CD44hi (E), consistent
with an activated phenotype. These data are representative of five
experiments performed with lymphocytes harvested from the CNS of five
individual mice with chronic demyelination at days 24 to 36 p.i.
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|
The frequency of CD4 T cells responding to a single epitope
[M(133-147)] is substantially higher than values obtained from
prior
studies. Many of these studies used limiting dilution assays
to
identify antigen-specific cells, and, as is the case for CD8
T cells,
use of this method substantially underestimates this
number (
5,
20,
21,
23). The recent development of more
sensitive methods to
measure antigen-specific T cells has led
to the reevaluation of antigen
specificity of CD4 T cells in other
viral infections. Approximately 3 to 10% of CD4 T cells in the
spleen and lymph nodes of mice infected
with lymphocytic choriomeningitis
virus (LCMV) are virus specific, as
measured by intracellular
staining for IFN-
(
21,
22,
27). This is in marked contrast
to results obtained with
limiting dilution assays, in which <1%
of CD4 T cells were determined
to be LCMV specific (
23). As
shown above, the
antigen-specific CD4 T-cell response was even
higher in the CNS of mice
infected with MHV-JHM, reflecting the
localized nature of the infection
caused by this virus. Few MHV-specific
CD4 or CD8 T cells were detected
in the CLN or spleen, probably
as a consequence of this
localization.
Although a substantial portion of the CD4 T-cell population in the
infected CNS was MHV specific, this did not account for
100% of the
lymphocytes at this site, particularly in mice chronically
infected
with the virus (Fig.
4). Nothing is known about the specificity
of the
CD4 T cells that do not recognize the three known MHV CD4
T epitopes.
CD4 T cells responsive to myelin-specific epitopes
have been identified
in mice with demyelination induced by Theiler's
murine
encephalomyelitis virus (
13). Although autoreactive
CD4
T cells have been identified only infrequently in MHV-infected
rodents (
25), such cells might be present in this putative
pool
of non-MHV-specific CD4 T cells and might contribute to the
chronic
demyelination observed in persistently infected
mice.
The kinetics of appearance of CD4 and CD8 T cells responding to each
MHV-specific epitope within the CNS were very similar,
but not
identical. This was particularly evident at days 6 and
7 p.i.,
when the expansion of CD8 T cells responding to epitopes
S(510-518)
and S(598-605) was greater than that of M(133-147)-specific
CD4 T
cells. These differences may reflect the critical role of
CD8 T cells
as direct antiviral effector cells. Alternatively,
they may represent
differences in trafficking or proliferative
capabilities of the two
subsets of cells or quantitative differences
in antigen presentation.
Another possibility is that the number
of precursor CD4 T cells able to
recognize epitope M(133-147)
is significantly greater in the
naïve T-cell population than
the number responding to either
CD8 T-cell epitope. As a consequence,
the response to epitope
M(133-147) would initially be more rapid,
although eventually the
MHV-specific CD8 T-cell response would
eclipse it. The data presented
in Fig.
2, showing little skewing
of V
usage in the epitope
M(133-147)-specific CD4 T-cell population
compared to that of
naïve splenocytes, are consistent with this
possibility.
In conclusion, these results show that MHV-specific CD4 T cells
comprise a large fraction of the CD4 T-cell population in
the infected
CNS and remain functional in persistently infected
animals. Further
investigations will be directed at determining
the precise role of
these MHV-specific, as well as any MHV-nonspecific,
CD4 T cells in the
process of chronic
demyelination.
| |
ACKNOWLEDGMENTS |
We thank Charles Lutz and Morris Dailey for critically reviewing
the manuscript and Justin Fishbaugh for help with FACS analysis.
This research was supported in part by grants from the National
Institutes of Health (NS36592 and AI43497) and the National Multiple
Sclerosis Society (RG2864-A-2). J.S.H. was supported by an NIH
institutional training grant (P32 AI 07533).
| |
FOOTNOTES |
*
Corresponding author: Department of Pediatrics,
University of Iowa, Medical Laboratories 2042, Iowa City, IA 52242. Phone: (319) 335-8549. Fax: (319) 335-8991. E-mail:
Stanley-Perlman{at}uiowa.edu.
| |
REFERENCES |
| 1.
|
Bergmann, C. C.,
J. D. Altman,
D. Hinton, and S. A. Stohlman.
1999.
Inverted immunodominance and impaired cytolytic function of CD8+ T cells during viral persistence in the central nervous system.
J. Immunol.
163:3379-3387[Abstract/Free Full Text].
|
| 2.
|
Bishop, G. A.,
L. M. Ramirez, and G. A. Koretzsky.
1993.
Growth inhibition by a B cell clone mediated by ligation of IL-4 receptors or membrane IgM.
J. Immunol.
150:2565-2574[Abstract].
|
| 3.
|
Butz, E. A., and M. J. Bevan.
1998.
Massive expansion of antigen-specific CD8+ T cells during an acute virus infection.
Immunity
8:167-175[CrossRef][Medline].
|
| 4.
|
Castro, R. F.,
G. D. Evans,
A. Jaszewski, and S. Perlman.
1994.
Coronavirus-induced demyelination occurs in the presence of virus-specific cytotoxic T cells.
Virology
200:733-743[CrossRef][Medline].
|
| 5.
|
Christensen, J. P., and P. C. Doherty.
1999.
Quantitative analysis of the acute and long-term CD4+ T-cell response to a persistent gammaherpesvirus.
J. Virol.
73:4279-4283[Abstract/Free Full Text].
|
| 6.
|
Cole, G.,
T. Hogg, and D. Woodland.
1995.
T cell recognition of the immunodominant Sendai virus NP324-332/Kb epitope is focused on the center of the peptide.
J. Immunol.
155:2841-2848[Abstract].
|
| 7.
|
Flynn, K. J.,
G. Belz,
J. D. Altman,
R. Ahmed,
D. L. Woodland, and P. C. Doherty.
1998.
Virus-specific CD8+ T cells in primary and secondary influenza pneumonia.
Immunity
8:683-691[CrossRef][Medline].
|
| 8.
|
Houtman, J. J., and J. O. Fleming.
1996.
Dissociation of demyelination and viral clearance in congenitally immunodeficient mice infected with murine coronavirus JHM.
J. Neurovirol.
2:101-110[Medline].
|
| 9.
|
Houtman, J. J., and J. O. Fleming.
1996.
Pathogenesis of mouse hepatitis virus-induced demyelination.
J. Neurovirol.
2:361-376[Medline].
|
| 10.
|
Lampert, P. W.,
J. K. Sims, and A. J. Kniazeff.
1973.
Mechanism of demyelination in JHM virus encephalomyelitis.
Acta Neuropathol.
24:76-85[CrossRef][Medline].
|
| 11.
|
Lane, T. E.,
M. T. Liu,
B. P. Chen,
V. C. Asensio,
R. M. Samawi,
A. D. Paoletti,
I. L. Campbell,
S. L. Kunkel,
H. S. Fox, and M. J. Buchmeier.
2000.
A central role for CD4+ T cells and RANTES in virus-induced central nervous system inflammation and demyelination.
J. Virol.
74:1415-1424[Abstract/Free Full Text].
|
| 12.
|
Lin, Y. M., and R. M. Welsh.
1998.
Stability and diversity of T cell receptor repertoire usage during lymphocytic choriomeningitis virus infection of mice.
J. Exp. Med.
188:1993-2005[Abstract/Free Full Text].
|
| 13.
|
Miller, S. D.,
C. Vanderlugt,
W. Begolka,
W. Pao,
R. Yauch,
K. Neville,
Y. Katz-Levy,
A. Carrizosa, and B. Kim.
1997.
Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreading.
Nat. Med.
3:1133-1136[CrossRef][Medline].
|
| 14.
|
Murali-Krishna, K.,
J. D. Altman,
M. Suresh,
D. Sourdive,
A. Zajac,
J. Miller,
J. Slansky, and R. Ahmed.
1998.
Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection.
Immunity
8:177-187[CrossRef][Medline].
|
| 15.
|
Oxenius, A.,
R. M. Zinkernagel, and H. Hengartner.
1998.
Comparison of activation versus induction of unresponsiveness of virus-specific CD4+ and CD8+ T cells upon acute versus persistent viral infection.
Immunity
9:449-457[CrossRef][Medline].
|
| 16.
|
Perlman, S.,
R. Schelper,
E. Bolger, and D. Ries.
1987.
Late onset, symptomatic, demyelinating encephalomyelitis in mice infected with MHV-JHM in the presence of maternal antibody.
Microb. Pathog.
2:185-194[CrossRef][Medline].
|
| 17.
|
Pewe, L.,
S. B. Heard,
C. C. Bergmann,
M. O. Dailey, and S. Perlman.
1999.
Selection of CTL escape mutants in mice infected with a neurotropic coronavirus: quantitative estimate of TCR diversity in the infected CNS.
J. Immunol.
163:6106-6113[Abstract/Free Full Text].
|
| 18.
|
Stohlman, S. A.,
C. C. Bergmann,
M. T. Lin,
D. J. Cua, and D. R. Hinton.
1998.
CTL effector function within the central nervous system requires CD4+ T cells.
J. Immunol.
160:2896-2904[Abstract/Free Full Text].
|
| 19.
|
Stohlman, S. A.,
C. C. Bergmann, and S. Perlman.
1998.
Mouse hepatitis virus, p. 537-557.
In
R. Ahmed, and I. Chen (ed.), Persistent viral infections. John Wiley & Sons, Ltd., New York, N.Y.
|
| 20.
|
Topham, D. J., and P. C. Doherty.
1998.
Longitudinal analysis of the acute Sendai virus-specific CD4+ T cell response and memory.
J. Immunol.
161:4530-4535[Abstract/Free Full Text].
|
| 21.
|
Varga, S., and R. Welsh.
1998.
Detection of a high frequency of virus-specific CD4+ T cells during acute infection with lymphocytic choriomeningitis virus.
J. Immunol.
161:3215-3218[Abstract/Free Full Text].
|
| 22.
|
Varga, S. M., and R. M. Welsh.
2000.
High frequency of virus-specific interleukin-2-producing CD4+ T cells and Th1 predominance during lymphocytic choriomeningitis virus infection.
J. Virol.
74:4429-4432[Abstract/Free Full Text].
|
| 23.
|
Varga, S. M., and R. M. Welsh.
1998.
Stability of virus-specific CD4+ T cell frequencies from acute infection into long term memory.
J. Immunol.
161:367-374[Abstract/Free Full Text].
|
| 24.
|
Wang, F.,
S. A. Stohlman, and J. O. Fleming.
1990.
Demyelination induced by murine hepatitis virus JHM strain (MHV-4) is immunologically mediated.
J. Neuroimmunol.
30:31-41[CrossRef][Medline].
|
| 25.
|
Watanabe, R.,
H. Wege, and V. ter Meulen.
1983.
Adoptive transfer of EAE-like lesions from rats with coronavirus-induced demyelinating encephalomyelitis.
Nature
305:150-153[CrossRef][Medline].
|
| 26.
|
Weiner, L. P.
1973.
Pathogenesis of demyelination induced by a mouse hepatitis virus (JHM virus).
Arch. Neurol.
28:298-303[Abstract/Free Full Text].
|
| 27.
|
Whitmire, J. K.,
M. S. Asano,
K. Murali-Krishna,
M. Suresh, and R. Ahmed.
1998.
Long-term CD4 Th1 and Th2 memory following acute lymphocytic choriomeningitis virus infection.
J. Virol.
72:8281-8288[Abstract/Free Full Text].
|
| 28.
|
Wu, G.,
A. Dandekar,
L. Pewe, and S. Perlman.
2000.
CD4 and CD8 T cells have redundant but not identical roles in virus-induced demyelination.
J. Immunol.
165:2278-2286[Abstract/Free Full Text].
|
| 29.
|
Wu, G. F., and S. Perlman.
1999.
Macrophage infiltration, but not apoptosis, is correlated with immune-mediated demyelination following murine infection with a neurotropic coronavirus.
J. Virol.
73:8771-8780[Abstract/Free Full Text].
|
| 30.
|
Xue, S., and S. Perlman.
1997.
Antigen specificity of CD4 T cell response in the central nervous system of mice infected with mouse hepatitis virus.
Virology
238:68-78[CrossRef][Medline].
|
| 31.
|
Xue, S.,
N. Sun,
N. van Rooijen, and S. Perlman.
1999.
Depletion of blood-borne macrophages does not reduce demyelination in mice infected with a neurotropic coronavirus.
J. Virol.
73:6327-6334[Abstract/Free Full Text].
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Journal of Virology, March 2001, p. 3043-3047, Vol. 75, No. 6
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.6.3043-3047.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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