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*
Department of Neurology, and
Division of Clinical Immunology and Rheumatology, University of Alabama, Birmingham, AL 35294;
Department of Immunology, St Jude’s Children’s Research Hospital, Memphis, TN 38105;
Max Planck Institute for Neurobiology, Martinsried, Germany; and
¶ Department of Pathology (Neuropathology), Albert Einstein College of Medicine, Bronx, NY 10461
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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TCR+ T cells that are
encephalitogenic in C57BL/6 (B6) mice. The encephalitogenic potential
of CD8+ MOG-specific T cells was established by adoptive
transfer of CD8-enriched MOG-specific T cells. These cells induced a
much more severe and permanent disease than disease actively induced by
immunization with pMOG35–55. CNS lesions in
pMOG35–55 CD8+ T cell-induced EAE were
progressive and more destructive. The CD8+ T cells were
strongly pathogenic in syngeneic B6 and RAG-1-/- mice,
but not in isogeneic 2-microglobulin-deficient mice.
MOG-specific CD8+ T cells could be repeatedly reisolated
for up to 287 days from recipient B6 or RAG-1-/- mice in
which disease was induced adoptively with <1 x 106 T
cells sensitized to pMOG35–55. It is postulated that MOG
induces a relapsing and/or progressive pattern of EAE by eliciting a T
cell response dominated by CD8+ autoreactive T cells. Such
cells appear to have an enhanced tissue-damaging effect and persist in
the animal for long periods. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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EAE has been induced in rodents by sensitization with a number of
myelin proteins, including myelin basic protein (MBP) (10, 11), proteolipid protein (PLP) (12, 13), myelin
oligodendrocyte glycoprotein (MOG) (14, 15, 16),
myelin-associated glycoprotein (17), and myelin
oligodendrocyte basic protein (18). Previous studies of
the functional characteristics of encephalitogenic effector cells
during EAE have focused on MBP- and PLP-reactive T cells. These studies
have led to the general consensus that, unlike autoimmune diabetes in
which both CD4+ and CD8+ T
cells participate (19, 20), effector T cells in EAE are
exclusively CD4+ and
TCR+ (21). Recently,
MOG-induced EAE has attracted increasing attention, particularly
because MOG-reactive T cells are readily found in the circulation in
multiple sclerosis (MS) patients (22, 23), and MOG-derived
synthetic peptides reproducibly induce EAE in a variety of mouse
strains. In particular, MOG induces forms of chronic and relapsing
demyelinating disease in mice (24, 25, 26) and primates
(27, 28), the latter having much in common with human MS.
Using similar experimental procedures, we have now shown that C57BL/6
(B6) mice immunized with a synthetic peptide representing residues
35–55 of MOG (pMOG35–55) consistently
generated CD8+TCR+
encephalitogenic T cells. We have also demonstrated that adoptive
transfer of enriched CD8+ MOG-specific T cells
from B6 mice induces a more severe clinical and pathologic disease
after adoptive transfer than disease induced by active immunization
with pMOG35–55.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B6, SJL/J, RAG-1-/-, MHC class
II-/-, and
2-microglobulin
(2m)-/- mice were
obtained from The Jackson Laboratory (Bar Harbor, ME), and housed in a
National Institutes of Health-approved and American Association for the
Accreditation of Laboratory Animal Care-accredited facility.
Cells and reagents
All T cells were cultured in RPMI 1640 medium (Life
Technologies, Grand Island, NY) supplemented with 10% selected FCS
(Life Technologies), 5 x 10-5 M 2-ME, and
penicillin/streptomycin (100 µg/ml). pMOG35–55
(MEVGWYRSPFSRVVHLYRNGK), pMOG40–54
(YRSPFSRVVHLYRNG), and synthetic peptide representing residues
178–191 of PLP (pPLP178–191) (NTWTTCQSIAFPSK) synthetic peptides were
produced by the Molecular Resource Center at St. Jude’s Children’s
Research Hospital (Memphis, TN). mAbs GK1.5 (specific for mouse CD4)
and 2.43 (specific for mouse CD8) were obtained from the American
Type Culture Collection (Manassas, VA). Abs specific for mouse
H-2Kb/H-2Db (28-8-6), mouse
I-Ab (M5/114), and mouse CD80 were purchased from
PharMingen (San Diego, CA). Recombinant dimers of the MHC class I
(H-2Db) molecule, recombinant human
2m, and synthetic peptide
NP366–374 (ASNENMETM) derived from influenza
virus were also obtained from PharMingen.
Active induction of EAE
Mice were immunized with pMOG35–55 peptide (200 µg per mouse) emulsified in CFA containing 0.6 mg Mycobacterium tuberculosis (H37Ra; Difco, Detroit, MI). After 48 h postimmunization, MOG-sensitized animals received a single i.p. dose of 400 ng of Pertussis toxin (Sigma, St. Louis, MO).
Adoptive transfer of T cells isolated from B6 mice with EAE actively immunized with pMOG35–55
To determine and characterize encephalitogenic T cells from pMOG35–55-immunized animals, T cells isolated from the draining lymph nodes and spleens of immunized animals were enriched by passage through nylon wool and restimulated in vitro with pMOG35–55 (20 µg/ml) presented by irradiated syngeneic spleen cells. After 3 days, activated T cell blasts were separated on a Ficoll gradient and injected (2 x 106 i.p) into naive B6 or RAG-1-/- mice.
T cell proliferation/inhibition assays
APC (irradiated syngeneic spleen cells, 2 x 105/well) were preincubated in 96-well flat-bottom microtiter plates with an optimal dose (20 µg/ml) of pMOG35–55. After 1 h, enriched T cells (4 x 104/well), prepared from lymph nodes or spleen by nylon wool adhesion, were seeded and further incubated for 48–72 h. The cultures were then pulsed with 1.0 µCi [3H]thymidine/well for 6 h and harvested, and the incorporated isotope was quantitated by liquid scintillation.
Depletion of T cell subsets by Ab-coated magnetic beads
Nylon wool-enriched splenic T cells were incubated with 10 µg/ml of either rat anti-mouse CD4 mAb (GK1.5) or normal rat Ig (control) for 30 min. Unbound Ab was removed by washing twice before the addition of magnetic biospheres coupled to goat anti-rat Ig (BioSource International, Camarillo, CA), incubating at 4°C, and agitating for 30 min. The tube of cells was then placed on a magnetic stand for 5 min, and cells free of magnetic particles were collected. The procedure was repeated 2–3 times as necessary.
Clinical evaluation of EAE
Animals were examined daily for weight loss and clinical signs. Animals were clinically graded as follows: 0 = no signs; 1 = partial loss of tail tonicity; 2 = loss of tail tonicity, difficulty in righting; 3 = unsteady gait and mild paralysis; 4 = hind-limb paralysis and incontinence; and 5 = moribund or death.
Flow cytometric detection of T cells binding to pMOG35–55 complexed with recombinant dimers of MHC class I (H-2Db) molecule
Dimeric MHC class I (H-2Db) used in this
study is a fusion protein between mouse H-2Db and
mouse IgG1. The recombinant protein was added to an equal amount of
human 2m at a final concentration of 0.15
mg/ml in the presence of an excess amount of testing peptide (1 mg/ml).
The mixtures were stored at 4°C for 24–48 h before use. Single color
staining was performed by incubating 5 x
105 cells with peptide-dimer complexes of 1.0
µg per staining at 4°C for 30 min. The cells were washed twice in
PBS containing 1% BSA and 0.1% sodium azide and restained with a
PE-labeled anti-mouse IgG1 Ab. The results are presented as forward
scatter (x-axis) vs fluorescence intensity
(y-axis).
Routine histology
For this, mice were anesthetized, bled, and perfused
with 25 ml PBS and 10 ml 4% paraformaldehyde in buffered PBS. Brains
and spinal cords were dissected out and fixed in 4% paraformaldehyde
before embedding in paraffin. Paraffin sections were stained with
hematoxylin/eosin and Luxol fast blue (for myelin). Immunocytochemistry
was performed on 3-µm paraffin sections, using a
biotin/avidin/peroxidase technique. For this, CNS tissue was examined
from seven representative animals from the experimental groups (Table I
). For detailed neuropathology, three
mice were sampled during the acute phase of
pMOG35–55-active EAE (19–24 days post
immunization (dpi)) during the acute phase of the disease; two
B6 mice with adoptive CD8+
pMOG35–55 EAE; and two
RAG-1-/- mice with adoptively transferred
CD8+ pMOG35–55 EAE were
studied during the chronic phase, 56 and 70 days post transfer (dpt).
At the time of sampling, animals were anesthetized with ether and
perfused through the heart with 20 ml of cold
PO4-buffered 2.5% glutaraldehyde. The
brain and spinal cords were removed, and thin slices were taken from
the cerebral hemispheres, cerebellum/brainstem, and spinal cord at C7,
Th2, L2, L5, L6, and S1. In addition, optic nerve and spinal nerve
roots were taken. The tissue samples were then postosmicated in 1%
osmium tetroxide, dehydrated, and embedded in epoxy resin.
One-micrometer epoxy sections stained with toluidine blue were prepared
from all levels for light microscope analysis.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Splenic T cells were prepared by passing through a nylon wool
column. CD4+ and CD8+ T
cells were separated by negative depletion method using Ab-coated
magnetic beads (see Materials and Methods). The
CD4+ and CD8+ T cells thus
obtained have the purity of >98%. When exposed to
pMOG35–55 and APC, both cell fractions responded
with proliferation (Fig. 1C).
When the pMOG35–55-activated cells were cultured
in IL-2-containing medium for 5–10 days, an overwhelming majority of
the proliferating cells expressed a surface phenotype
TCR+CD4-CD8+
(Fig. 1, A and B). To determine whether the
dominant CD8+ cells were the major pathogenic
effectors and that the disease was not the result of the minor
CD4+ population, we depleted CD4 T cells from
immunized animals using magnetic biospheres, and the remaining
CD8+ T cell populations were stimulated with an
optimal dose of pMOG35–55 and APCs. The results
showed that depletion of CD4 T cells did not affect the pathogenic
activity of enriched CD8+ T cells activated by
pMOG35–55. Alternatively, we administered
MOG-reactive T cells to
2m-/- mice and
compared them with B6 mice. Three separate experiments with a total of
nine 2m-/- mice and
>100 B6 mice were conducted. All the
2m-/- mice studied
were resistant to EAE adoptively induced by CD8+
MOG-specific T cells (Fig. 2).
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B) and re-isolated (Fig. 3C) from the recipient animals, indicating that such T cells
may have an increased ability to survive in vivo. FACS determination of
the MOG-specific T cells re-isolated from recipient animals’ spleens
showed that the re-isolated T cells were predominantly
CD8+ (Fig. 3C). We also determined the
number of pMOG35–55-reactive T cells that were
restricted by MHC class I Ags by their binding ability to recombinant
H-2Db dimers. Thus, 20 days after the
immunization of pMOG35–55/CFA, the animals were
sacrificed, and the splenic T cells were enriched by passing through
nylon wool. Such T cells were incubated with irradiated spleen cells
(APC) and 20 µg/ml pMOG35–55 for 48 h,
separated on a Ficoll gradient, and cultured in IL-2-containing medium.
The proliferating cells were stained with
MOG35–55-H-2Db. The
percentage of positive cells was quite low before the cells were
expanded in IL-2-containing medium. However, 
20–60% of the total T
cells were stained by
MOG35–55-H-2Db, but not
the same class I molecules (H-2Db) bound by a
control peptide NP366–374 derived from influenza
virus and known to bind H-2Db (29, 30) after a 7- to 10-day culture in IL-2-containg medium (Fig. 4).
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Massive CNS inflammation and overinfiltration of macrophage/microglia in the CNS
Most, if not all, B6 mice developed a chronic, relapsing EAE after
immunization with 200 µg of synthetic peptide
pMOG35–55 emulsified in CFA (24).
The duration of the disease varied, and this was closely related to the
dose of M. tuberculosis (H37RA). In most cases, mice
immunized with a similar dose of pMOG35–55 but
<0.6 mg of H37RA, had a shorter duration of disease, varying from 20
to 60 days. Remarkably, both clinical signs and pathologic changes
induced by adoptive transfer of MOG-specific T cells were much more
severe than those induced by active immunization with peptide. Less
than 1 x 106 MOG-specific T cells were
found to cause a severe paralytic disease in naive B6 and
RAG-1-/- mice (Table I
). Examination by routine
histology revealed that massive CNS infiltration, myelin degeneration,
and demyelination were consistently identified in animals with
adoptively transferred EAE (Fig. 5B), features which in most
cases were milder in actively induced disease. Immunohistochemical
studies showed that an overwhelming majority of the CNS infiltrating
cells were reactive with isolectin B4 (Fig. 5C), a marker of
microglia and inflammatory macrophages (31, 32). The ratio
between isolectin B4- and CD3-stained cells was >10:1. Kinetic studies
revealed that CD3+ cells disappeared much earlier
in comparison to isolectin B4-staining cells from the CNS, even though
the disease remained relapsing or progressive (Fig. 5C).
Pathologic expression in chronic phases of actively induced disease
varied significantly in that both the duration and relapse rate of the
disease were not predictable (data not shown). We have also determined
CD4+ and CD8+ cells in
brain lesions, using immunocytochemical staining; however, we could not
show a significantly increased infiltration of
CD8+ cells in the CNS inflammation (data not
shown).
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Histopathologic analysis of 1-µm epoxy sections showed that
lesions within the CNS of pMOG35–55 actively and
adoptively induced EAE differed markedly (Table I). In the actively
induced form at initial onset of signs in B6 mice, lesions occurred
mostly in the spinal cord and were diffusely distributed in subpial
regions. They displayed an infiltrate comprising large mononuclear
cells, small lymphocytes, and a modest number of neutrophils (Fig. 6A). Demyelinated axons were
common, and around the margins of affected areas, occasional fibers
undergoing Wallerian degeneration (vacuolation of myelin sheath
and disintegration or swelling of the axon) were in evidence. By 6 days
after onset of actively induced EAE in B6 wild-type mice, lesions were
well demarcated, the CNS infiltrate comprised small lymphocytes, large
mononuclear cells, and a few plasma cells, but neutrophils were rare to
absent. Demyelinated axons were present, as was a narrow zone of fibers
undergoing Wallerian degeneration at the lesion edge (Fig. 6B). This zone contained large myelin-bound vacuoles, some
of which surrounded much enlarged dystrophic and degenerating
axons.
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C) where many neutrophils and
monocytes, plus the occasional small lymphocyte, constituted the CNS
infiltrate. Lesions in the spinal cord of CD8+
pMOG35–55 mice at the same interval (after 2
days of signs) were also more extensive than in their actively induced
counterparts, being extensively infiltrated, particularly by
neutrophils, and displayed a broader zone of nerve fiber damage. Large
mononuclear cells and neutrophils percolated throughout the adjacent
myelinated white matter, and small lymphocytes were rare (Fig. 6D). pMOG35–55 adoptively transferred
EAE did not remit, and 15 days after onset, large areas of ongoing
nerve fiber destruction rich in infiltrating cells were still in
evidence within the CNS parenchyma (Fig. 7A). Within the leptomeningeal
space, an extensive, closely packed population of infiltrating cells,
many of them macrophages laden with lipid droplets and myelin debris,
was also seen. This extensive, later involvement of macrophages
probably coincided with the enhanced B4 (isolectin) positivity seen by
immunocytochemistry (see above). At higher magnification, demyelinated
axons could be discerned (Fig. 7B), but these were usually
overshadowed by the extensive Wallerian degeneration.
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C). The CNS infiltrate contained the occasional neutrophil
and plasma cell but mainly comprised large mononuclear cells and
macrophages (Fig. 7, C and D). Apparently
well-preserved, demyelinated axons existed alongside fibers that had
undergone Wallerian degeneration (Fig. 7D). In one adoptive
EAE animal sampled at 76 dpt, both active and reparatory lesions could
be seen. Active lesions probably reflected relapsing lesion activity
and presented as areas of ongoing demyelination intensively infiltrated
by large mononuclear cells and a few small lymphocytes, neutrophils,
and plasma cells (Fig. 7E). Again, demyelinated axons
coexisted with fibers displaying early and advanced Wallerian
degeneration and macrophages laden with myelin debris (Fig. 7F). Elsewhere in the same spinal cord at 70 dpt, areas of
longer-standing disease displayed CNS remyelination and fibrous
astrogliosis (scarring) (Fig. 7G). Even in these areas of
myelin repair, low grade inflammatory actively (mainly by large
mononuclear cells) was in evidence.
In general, the blood-brain barrier remained structurally intact and
widespread red cell extravasation (hemorrhage) was not a marked feature
of either the active or adoptive forms of
pMOG35–55 EAE. However, in a few lesions from
animals sampled during the acute phase of adoptive disease, an
occasional extravasated red cell was detected (Fig. 6D),
indicating that this form of the disease appeared to have a greater
effect upon the blood-brain barrier.
Persistence of MOG-specific T cells in animals actively immunized with pMOG35–55 or in recipient B6 mice adoptively transferred with MOG-specific T cells
In parallel with chronic disease expression, MOG-specific T cells
could be detected in the draining lymph nodes and the spleen of
immunized animals for >6–8 mo after single immunization. This
contrasted significantly with MBP-induced EAE in the Lewis rat in which
MBP-reactive T cells became undetectable following the acute phase of
the disease (9–20 dpi). pMOG35–55-specific T
cells were readily detectable in both spleen and lymph node >240 days
after immunization (Fig. 3A). After activation, splenic T
cells from MOG-immunized mice remained fully encephalitogenic after
>240 dpi, when tested by adoptive transfer into naive recipients (data
not shown).
Delayed onset of adoptively transferred EAE in RAG-/- mice
The onset of transferred disease in B6 mice regularly started at
7–8 days after cell injection. In contrast, initiation of a
transferred disease in RAG-1-/- mice varied
greatly. In four separate experiments, a total of 15
RAG-/- mice were studied. All mice had delayed
onset, varying from weeks to months. It was not unusual to observe
recipient RAG-1-/- mice apparently healthy for
60–80 days after injection of MOG-specific T cells, after which they
developed clinical signs (Fig. 8). Once
initiated, the disease was mostly fluctuating and/or progressive in
RAG-1-/- mice. The longest observation made was
of animals persistently paralyzed for >300 days.
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Following immunization of B6 mice with
pMOG35–55, draining lymph node cells responded
specifically to the immunizing peptide
pMOG35–55, but not to a peptide
MBP68–88, derived from guinea pig MBP (Fig. 9A). Ab blocking assays
demonstrated that the proliferation of MOG-specific T cells was
essentially completely blocked by Abs specific for MHC class I
molecules (28-8-6) and by Abs specific for CD80, whereas Abs specific
for MHC class II (M5/114) showed no significant inhibitory effect (Fig. 9B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TCR+, which, upon
transfer to syngeneic naive animals, cause paralytic disease. This has
led to the generally held view that effector cells in EAE are
invariably CD4+TCR+
cells. Recent studies have shown that T cell subsets reactive to myelin
PLP contain CD8+ cells (35). It was
also observed that T cells infiltrating active MS lesions are dominated
by CD8 T cells (36). Here, we provide strong evidence that
a synthetic peptide of MOG has the unexpected ability to induce
CD8+ encephalitogenic T cells. Adoptive transfer
of MOG-specific T cells caused a much more severe and progressive form
of EAE (particularly histopathologically) than active immunization of
mice for disease induction, and such T cells could be consistently
re-isolated from recipient animals.
Because the above finding is in marked contrast to our earlier studies
using dozens of peptides derived from other myelin Ags such as MBP and
PLP, which elicited reactive populations overwhelmingly dominated by
cells of the CD4+TCR+
phenotype, we made a special effort to verify that
CD8+ MOG-specific T cells were indeed pathogenic.
The encephalitogenic activity observed was not due to the presence of a
small fraction of CD4+ MOG-specific T cells in
the T cell lines. First, transfer of as few as 0.5 x
106 CD8 T cells to naive B6 or
RAG-1-/- mice readily induced paralysis in
syngeneic recipients, but not in isogeneic
2m-/- mice.
Presumably, due to the failure of these latter mice to express intact
MHC class I molecules, CD8+ effector T
cells did not remain functionally intact (37). Second,
ablation of CD4+ cells from the transferred T
cell population had no effect on the development of EAE in recipients.
Indeed, in adoptively transferred mouse EAE, the minimal number of
CD4+ cells needed to induce disease is in the
range of 5 x 106; it is unlikely that a
small percentage of CD4+ cells from a total of
0.5 x 106 CD8-dominated cells would account
for the disease activity. Third, an increased number of
pMOG35–55-activated T cells binds to recombinant
class I molecules (H-2Db) bound by
pMOG35–55, but not to the same MHC molecules
bound by a control peptide NP366–374. It is
necessary to point out that our conclusion that
CD8+ MOG-specific T cells played a major
pathogenic role in EAE did not exclude a pathogenic role for
CD4+ MOG-specific T cells, because
CD4+ cells may well be required for the efficient
recruitment of naive autoreactive T cells in vivo. For example, we
could have shown that MHC class II-/- mice are
susceptible to adoptively transferred disease induced by
CD8+ MOG-specific T cells, but they are resistant
to actively induced disease (data not shown). These observations
indicate that CD4+ cells are essential for the
initiation of disease, and/or development of CD8+
effector cells may need the help of CD4+ T cells;
however, once activated, CD8+ encephalitogenic T
cells can cause disease in the absence of CD4 T cell help. Studies are
underway to determine whether the two MOG-specific T cell subsets
examined herein have other synergistic effects in the pathogenesis of
EAE and whether blockade of the progression of EAE will be more
effective if CD8+ encephalitogenic T cells are
targeted.
Although MBP is the most commonly used Ag in the induction of EAE, recent studies have demonstrated encephalitogenic activity in a much broader range of myelin Ags, including PLP, myelin-associated glycoprotein, MOG, and myelin oligodendrocyte basic protein. Moreover, individual myelin proteins may exist as multiple isoforms and isomers generated by alternative exon use or posttranslational modification (38, 39, 40), thus forming "new autoantigens" that induce EAE by eliciting distinct or different subsets of pathogenic T cells (41). It remains to be determined whether the pathogenesis of the human disease, MS, involves more than one myelin protein, depending on the genetic makeup of the patients and environmental factors predisposing disease development. It is also important to determine whether different myelin proteins, or different isomers of a given myelin protein, induce similar disease by eliciting different immune responses, perhaps involving distinct pathogenic mechanisms.
Due to the fact that growth factors promoting
CD8+ T cell expansion in vitro are less well
characterized than those promoting CD4+ cells,
and that CD8+ encephalitogenic T cell lines are
as yet unavailable, most treatment regimens of EAE have been linked to
the study of pathogenic CD4+ T cells and have
targeted CD4+ cells. For example, the
identification of factors important for promoting or inhibiting the
activation of CD4+-autoreactive T cells has been
the subject of many reports. It is reasonable to assume that these same
identified factors may not have relevance in the activation of
CD8+-autoreactive T cells. Indeed, our
preliminary results have also demonstrated that not only are the
recognition or function of CD8+-pathogenic T
cells restricted by different MHC molecules, but that inflammatory
molecules, such as TGF-1 and IL-15, have distinct effects on
CD4+- and CD8+-autoreactive
T cells (data not shown).
Previous studies using EAE models induced by MBP have shown that the
dominant autoaggressive cells are CD4+ (42, 43), and that the recognition of CD4+ T
cells requires a trimolecular interaction among TCR, antigenic peptide,
and MHC class II. It has been hypothesized that autoaggressive cells in
EAE may attack parenchymal cells with the potential to express MHC
class II molecules (44). In this study, we have shown that
CD8+ MOG-specific T cells had a wide range of
cytotoxic activity. They have been shown to be cytolytic for
astrocytes, oligodendrocytes, and a number of tumor target cell lines,
and the effect is not Ag dependent (data not shown). It appears that
the cytolytic activity of CD8+ MOG-specific T
cells is less restricted than that of
CD4+-encephalitogenic T cells, the latter only
able to induce killing when target cells (e.g., astrocytes) are
preinduced for expression of MHC class II. The underlying mechanism for
the enhanced pathology encountered in adoptively transferred animals
was perhaps related to an increased, nonspecific cytotoxic effect
exerted by CD8+ T cells that led to a progressive
bystander destructive effect upon nerve fibers, rather than a specific
demyelinative process. Thus, although reparatory processes were in
place, they were overridden by ongoing destruction. Moreover, the
prolonged involvement of neutrophils in adoptive EAE may be of
pathogenetic significance. In active EAE, polymorphonuclear cell
invasion is brief, transient, and precedes macrophage entry
(45). Thus the more severe and protracted involvement of
polymorphonuclear cells and macrophages in the present CD8 paradigm may
bespeak widespread cytotoxicity and may belie the observed extensive
and long-lasting isolectin reactivity in lesion areas. We have also
determined the infiltration of CD4+ and
CD8+ cells in brain lesions; however, we could
not show a significantly increased infiltration of
CD8+ cells in the CNS inflammation. Conceivably,
this has been due to the fact that >95% of infiltrating cells in the
CNS inflammation are nonspecifically recruited as previously reported
(46, 47). One unexpected observation from this study was
that adoptive transfer of CD8+
pMOG35–55-reactive T cells from B6 donors into
RAG-1-/- mice caused a delayed onset of
disease. We are currently investigating whether such a unique disease
pattern was due to a lack of regulatory T cells (48, 49),
functionally antagonistic to autoreactive cells in RAG-1-deficient
mice. Previous studies have shown that MBP-reactive T cells have a
skewed TCR usage, frequently favoring the expression of V8.2.
However, our analysis of three
pMOG35–55-specific T cell lines did not reveal
any similar skewing.
We have shown that an increased number of
MOG35–55-stimulated T cells from MOG-immunized
animals were specifically stained by
MOG35–55-H-2Db
(30) (Fig. 4). Such an observation supports the notion
that MOG35–55 activates an increased number of
CD8+ T cells. However,
pMOG35–55 is a 20-mer, which is much longer than
the theoretical peptide length necessary for fitting the MHC class I
groove and for stimulation of CD8+ T cells
(50, 51). In contrast, a recent report has shown that
longer peptides can be accommodated in the MHC class I binding site by
a protrusion mechanism (52), a mechanism that may explain
our own observation. We are currently determining whether truncated
pMOG35–55 peptides containing essential amino
acid sequences will fit better into the binding groove of MHC class I
molecules, show more intense staining by FACS analysis, and exert
stronger stimulatory effects on MOG-specific T cells. Our preliminary
studies indicate that truncated pMOG40–54
peptides have increased stimulating activity for
CD8+, but not CD4+,
MOG-specific T cells. Such a study should allow us to determine whether
activation of CD8 MOG-specific T cells requires a specific CD4 response
and whether disease progression requires interactive CD4 and CD8
responses.
In summary, CD8++
cells comprise a large fraction of the encephalitogenic T cells in
MOG-induced EAE. This newly established experimental paradigm should
allow us to explore the mechanism by which
CD8+-autoreactive T cells mediate this disease,
and to determine immune perturbations elicited by
CD4+- and CD8+-pathogenic T
cells, respectively.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Deming Sun, Department of Neurology, 1046 THT, 1900 University Boulevard South, University of Alabama, Birmingham, AL 35294. E-mail address: dsun{at}uab.edu
3 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; 2m, 2-microglobulin; dpi, day(s) postimmunization; MOG, myelin oligodendrocyte glycoprotein; pMOG35–55, synthetic peptide representing residues 35–55 of MOG; PLP, proteolipid protein; pPLP178–191, synthetic peptide representing residues 178–191 of PLP; MS, multiple sclerosis; MBP, myelin basic protein; dpt, days post transfer.
Received for publication January 9, 2001. Accepted for publication April 2, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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