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From the Department of Periodontology, Faculty of Dentistry, Niigata University, Niigata, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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24JQ invariant T cell
receptor (TCR) has been reported to have a regulatory role in certain
autoimmune diseases. Therefore, we investigated the proportion
of the invariant V24JQ TCR within the V24 T cell population in
periodontitis lesions and gingivitis lesions using single-strand
conformation polymorphism methodology. NK T cells were identified with
a specific JQ probe whereas the total V24 TCR was identified
using an internal C probe. NK T cells were a significant proportion
of the total V24 population both in periodontitis lesions and to a
lesser extent in gingivitis lesions but not in the peripheral blood of
either periodontitis patients or nondiseased controls.
Using immunohistochemistry, some of V24+ cells
in the periodontitis lesions seemed to associate with CD1d+
cells, which are specific antigen-presenting cells for NK T
cells. Although the mechanism underlying the elevation of NK T cells in
periodontitis and in gingivitis lesions remains unclear, it can
be postulated that NK T cells are recruited to a play regulatory role
in the immune response to bacterial infection.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recently a unique lymphocyte population
designated natural killer T cells (NK T cells) has been characterized.
NK T cells express common markers for NK cells and the invariant
V-J T cell receptor (TCR) both in mice and
humans,8-13
Human invariant V24JQ T cells are
homologous to the murine V14J281 NK 1.1+ T cells that have a TCR
chain in which the V14 segment is rearranged to pair with
J281 with no N-region diversity.14-16
These NK T cells
have functionally important roles in vivo. A direct
relationship exists between a deficiency in NK T cells and
susceptibility to type 1 diabetes in nonobese diabetic
mice17-20
and in humans.21
A deficiency in
NK T cells has also been implicated in some other autoimmune diseases
including autoimmune gastritis22
and lupus-like
disease23,24
in mice and in humans with systemic
sclerosis.25
These studies suggest a role for NK T cells
in the regulation of autoimmune diseases.
We have previously demonstrated that the frequency of seropositivity and the antibody titer to human heat shock protein (hsp) 60 and Porphyromonas gingivalis GroEL, a periodontopathic bacterial homologue of human hsp60, were significantly higher in periodontitis patients than in periodontally healthy controls.26 Furthermore, affinity-purified serum antibodies to human hsp60 and P. gingivalis GroEL from selected patients reacted with P. gingivalis GroEL and human hsp60, respectively, indicating cross-reactivity of antibodies. In addition we found a higher frequency of hsp60- and P. gingivalis GroEL-reactive T cell clones in peripheral blood mononuclear cells (PBMCs) of periodontitis controls compared with periodontally healthy patients. Analysis of the nucleotide sequences of the CDR3 region in the T-cell receptor ß-chain clearly demonstrated that the identical T cell receptors were used between human hsp60-reactive peripheral blood T cells of periodontitis patients and periodontitis lesion-infiltrating T cells of the same patients (Yamazaki K, Ohsawa Y, Tabeta K, Ito H, Ueki K, Yoshie H, Seymour GJ, manuscript in preparation). These results suggest that an immune response based on the molecular mimicry between P. gingivalis GroEL and human hsp60 may play some role in periodontitis. Heat shock proteins, particularly the hsp60 family of proteins, are thought to play important roles in the causal relationship between microbial infections and autoimmunity because of conservation of the amino acid sequence during evolution and their strong immunogenicity. To date, there have been a number of reports regarding the role of hsps and autoimmune diseases.27
These studies led us to speculate that NK T cells may play an important
role in regulating the autoimmune response in chronic inflammatory
periodontal disease (periodontitis). Therefore, in the present study we
investigated the frequency of NK T cells in both gingivitis and
periodontitis lesions and demonstrated that the frequency of invariant
V24JQ TCR-expressing T cells is higher in periodontitis tissues
and to a lesser extent in gingivitis tissues than in autologous
peripheral blood, suggesting a preferential accumulation of NK T cells
in chronic inflammatory periodontal disease tissues.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Gingival tissue samples were obtained at the time of periodontal surgery (flap surgery) from 15 patients with moderate to severe periodontitis (mean age, 40.4 ± 9.9 years; range, 26 to 55 years) referred to the periodontal clinic of Niigata University Dental Hospital. All patients were classified as having chronic periodontitis with no systemic disorders. The mean probing depth, probing attachment level, and bone resorption were 6.5 ± 1.4 mm (range, 4 to 9 mm), 7.5 ± 1.7 mm (range, 4 to 10 mm), and 58.2 ± 27.1% (range, 10 to 100%), respectively. Approximately 100 mg of tissue containing the area of inflammatory cell infiltrate from each specimen was immediately frozen in liquid nitrogen and stored at -80°C until RNA separation. PBMCs were separated by Ficoll-Paque density gradient centrifugation from 10 ml of autologous peripheral blood. PBMCs were also separated from 12 periodontally healthy controls (mean age, 38.0 ± 7.7 years; range, 30 to 49 years) with probing attachment level <4 mm and minimal bone resorption at all sites. A small piece of marginal gingival tissue was also obtained from the second or third molar site from nine of the controls. Previous studies have shown that apparently clinically healthy gingiva display histological evidence of inflammation similar to that seen in marginal gingivitis.28 Subsequently these tissues were referred to as gingivitis tissues. Informed consent was obtained from all patients and controls before inclusion in the study.
RNA Separation and cDNA Synthesis
Total RNA from gingival tissues and PBMCs was separated by using Isogen (Nippon Gene, Tokyo, Japan) according to the manufacturer’s instructions. The RNA samples were further purified by successive treatment with DNase I (Life Technologies, Inc., Gaithersburg, MD), phenol/chloroform/isoamylalcohol (Life Technologies, Inc.) and ethanol sedimentation.
The first strand cDNA was synthesized using M-MLV reverse transcriptase (Life Technologies, Inc.) and 50 µmol/L of random hexanucleotides (Takara Shuzo Co., Ltd., Shiga, Japan) from 2 µg of total RNA in the reaction buffer (Life Technologies, Inc.) containing 50 mmol/L Tris-HCl (pH 8.3), 75 mmol/L KCl, 3 mmol/L MgCl2, supplemented with 0.5 U RNase inhibitor, 0.1 mol/L dithiothreitol, and dNTP (each at 0.5 mmol/L). The reaction mixture was incubated at 37°C for 60 minutes and then heated at 95°C for 5 minutes.
Polymerase Chain Reaction (PCR) Amplification of TCR V24 Gene
PCR amplification of cDNA was performed using oligonucleotide
primers specific for V24
(5'-GATATACAGCAACTCTGGATGCA-3')14
and C
(5'-AATAGGTCGACAGACTTGTCACTGGA-3').29
The reaction
mixture, prepared on ice contained 1x EX Taq buffer (Takara
Shuzo Co., Ltd., Shiga, Japan), 0.2 mmol/L of each dNTP, 0.4 µmol/L
of each primer, 2.4 µl of cDNA, and 0.35 U of EX Taq DNA
polymerase (Takara Shuzo Co.) in a total volume of 15 µl. The PCR
reaction was performed using a DNA thermal cycler (PCR Thermal Cycler
MP; Takara Shuzo Co.). The amplification cycle profile was as follows:
denaturation at 94°C for 10 seconds, annealing at 60°C for 20
seconds, and extension at 72°C for 30 seconds. The durations of
denaturation in the first cycle and extension in the last cycle were
extended for 7 minutes.
Single-Strand Conformation Polymorphism (SSCP) Analysis
After 35 cycles of amplification, the amplified TCR V24 gene
was diluted (1:39) in a denaturing solution (95% formamide, 10 mmol/L
ethylenediaminetetraacetic acid, 0.1% bromophenol blue, 0.1%
xylenecyanol) and kept at 90°C for 2 minutes. The diluted samples (2
µl) were electrophoresed in nondenaturing 4% polyacrylamide gels
containing 10% glycerol. The gel was run at 35 W constant power for
100 minutes. After electrophoresis, the DNA was transferred to
Immobilon-S (Millipore Intertech, Bedford, MA), and hybridized with
biotinylated JQ probe (5'-ACCCTGGGGAGGCTATACTT-3'), streptavidin,
biotinylated alkaline phosphatase, and a chemiluminescent substrate
system (Phototope Star Detection Kit; New England Biolabs, Beverly,
MA). The membrane was then exposed to X-ray film (RX-U; Fuji Photo Film
Co., Ltd., Tokyo, Japan). The membrane was reprobed using biotinylated
common C probe (5'-GAACCCTGACCCTGCCGTGTACC-3') and visualized as for
JQ probe.
Image Analysis
The X-ray films were photographed, and their image data were
analyzed using computer software (NIH image version 1.62, Research
Services Branch, National Institutes of Health, Bethesda, MD). To
improve the accuracy of the analysis, the relative amount of
V24JQ gene expression was calculated as the ratio to the total
V24 gene expression that is the amount of V24-C PCR product.
Briefly, using gel plotting macros, the total area of bands and smear
of each lane on the gels hybridized with internal C probe was
calculated and the area of V24JQ was divided by the total area.
The relative expression of invariant TCR V24JQ gene to total TCR
V24 was compared between the gingival tissue and peripheral blood
samples.
Sequence Analysis of TCR V24 Gene
A small area of the dried SSCP gel, corresponding to the position
of the invariant V24JQ TCR, was cut out from selected samples.
The gel piece was immersed in 50 µl of 10 mmol/L Tris-HCl and 0.1
mmol/L of ethylenediaminetetraacetic acid in a centrifuge microtube and
was heated at 80°C for 20 minutes. The extract was vortexed and
centrifuged. The supernatant was then subjected to a second PCR
amplification for 40 cycles. Amplified DNA was purified by agarose gel
electrophoresis and the subsequent use of DNA purification kit. The
recovered DNA fragments were subcloned into pCR 2.1 vector and
transfected into TOP10F' (Invitrogen Co., San Diego, CA). After
blue/white screening of recombinant plasmids on
X-galactoside/isopropyl-thiogalactoside indicator plate, single, white
colonies were picked and grown for 12 hours at 37°C on LB broth.
After purification of plasmid, the correct inserts in positive clones
were confirmed by PCR amplification with V24 and C primers, and
were used for automated sequencing (Pharmacia Biotech, Uppsala Sweden).
A clone bearing invariant TCR V24JQ sequence was used as a
control in subsequent experiments.
Immunohistochemistry
To estimate the proportion of TCR V24-bearing T cells in
periodontitis tissues, gingival specimens were collected from a further
seven patients, and serial cryostat sections were prepared. The
clinical profile of these patients was similar to those analyzed for
V24JQ gene expression. The inflammatory gingival tissues were
taken so as to analyze the same area as the gene expression being
analyzed. Monoclonal anti-V24 (Clone NOR3.2; Cosmo Bio Co., Ltd.,
Tokyo, Japan), anti-CD1d (Pharmingen, San Diego, CA) and anti-CD3
(DAKO, Glostrup, Denmark) were used for single staining by an
avidin-biotin-immunoperoxidase (ABC-PO) method. Double staining of
V24 and CD1d was performed by using combined an ABC-PO method and an
alkaline-phosphatase anti-alkaline-phosphatase (APAAP) method.
After rehydration in 0.05% Tris-buffered saline (pH 7.6) and blocking
with normal rabbit serum (DAKO), the sections were incubated with
primary monoclonal antibody (mAb) at a predetermined dilution followed
by rabbit anti-mouse immunoglobulins (DAKO) and finally with monoclonal
mouse APAAP (DAKO). Color was developed with an alkaline-phosphatase
substrate III kit (Vector, Burlingame, CA). For double staining, the
sections were first incubated with monoclonal anti-V24 as first
primary mAb at a predetermined dilution followed by biotinylated horse
anti-mouse IgG (Vector) and finally with ABC-PO. After color
development using 0.005% 3,3-diaminobenzidine in Tris-HCl buffer (pH
7.2) containing 0.01% hydrogen peroxide, an APAAP method using
monoclonal anti-CD1d as a second primary mAb followed. Incubation for
30 minutes at room temperature was followed by washing for 10 minutes
in Tris-buffered saline (pH 7.6). Nuclei were counterstained with
hematoxylin. Endogenous peroxidase and alkaline phosphatase activities
were blocked by 0.17% NaN3 and 1 mmol/L
levamisole, respectively.
Cell Analysis
The total number of V24-positive and CD3-positive cells were
counted on each section at a magnification of x400. The proportion of
V24-positive cells to the total number of CD3-positive cells was
calculated. Counts were repeated three times and minimal variation was
confirmed.
Statistical Analysis
The relative expression of invariant TCR V24JQ gene was
compared between gingival tissues and peripheral blood samples, and
between patients and controls. The data were analyzed using unpaired
t-test. The statistical significance risk rate was set at
P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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24JQ in Gingival Tissue and
Peripheral Blood
In a preliminary experiment, we examined whether a probe for JQ
can in fact detect invariant TCR V24JQ sequence. The small area
of dried SSCP gel, corresponding to the position of the band was cut
out. DNA extracted from a piece of gel was amplified by PCR using
V24 and C primers, purified by agarose gel electrophoresis and a
subsequent DNA purification kit. The DNA was subcloned using a
commercial kit (Invitrogen Co., San Diego, CA) and sequenced. As shown
in Table 1
, all clones demonstrated
V24JQ sequence specific to NK T cells, suggesting that this
method is appropriate.
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24-Bearing T Cells in Peripheral Blood and
Gingival Tissues
We tried to identify the clonality of
V24+ T cells in gingival tissues and
peripheral blood of both periodontitis patients and controls using an
internal C probe that can detect all of the
V24+ T cells. As shown in the top panels of
Figure 1, A and B
, samples of peripheral
blood from both controls and periodontitis patients demonstrated a few
bands on a smear background or a dense smear without appreciable bands.
This indicates either relatively few clonotypes are present in
peripheral blood or heterogeneity of the V24+
T cells. Because there was no difference in the number of clonotypes
between periodontitis patients and controls, it seems that clonality of
peripheral blood T cells could not be affected by oral bacteria.
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24 clonotypes,
which is identifiable as a number of distinct bands, was found in both
the periodontitis and gingivitis tissues (Figure 1, C and D
; top). This
indicates that the clonality of V24-bearing T cells did not differ
between periodontitis tissues and gingivitis tissues.
Detection of the Invariant V24JQ TCR
After removing the C probe, the membrane was re-hybridized with
the biotinylated probe for the invariant V24JQ sequence. As shown
in bottom panels of Figure 1
, the invariant V24JQ TCR was
detected in peripheral blood and gingival tissue samples from both
controls and periodontitis patients. However, the frequency of samples
containing the V24JQ TCR was lower in peripheral blood than
gingival tissue samples (Figure 1, A and B)
. Although there was no
difference in the frequency and the density of bands corresponding to
the invariant V24JQ in the peripheral blood of patients and
controls, those of gingival tissue samples were higher in periodontitis
tissues compared with gingivitis tissues. In gingivitis tissues, two
samples (controls b and h) demonstrated absence of the band
corresponding to the invariant V24JQ TCR. Although the density of
the invariant V24JQ TCR was higher in gingival tissues than in
peripheral blood of controls a and e, it did not demonstrate a big
difference between the gingival tissues and peripheral blood of
controls c, d, f, and g. Therefore, although the intensity of a band
does not necessarily represent the absolute number of clones, these
results generally indicate that the frequency of the invariant
V24JQ-bearing NK T cells increased in periodontitis lesions and
to a lesser extent in gingivitis lesions. Several faint bands appeared
at different positions of the invariant V24JQ in most gingival
tissue samples (Figure 1, C and D
; bottom). Although these bands were
at a similar position (arrowhead), another unique band did appear in
patients 8 and 14 (open arrowhead).
To compare the proportion of the invariant V24JQ-bearing NK T
cells within the V24 T cells between periodontitis and gingivitis
lesions, semiquantitative analysis was performed. As shown in Figure 2
, relative gene expression of
V24JQ was slightly but significantly higher in periodontitis
tissues than gingivitis tissues (P = 0.016). No
significant difference was observed either for peripheral blood between
patients and controls or between gingivitis tissues and peripheral
blood. Thus, it is apparent that an increased proportion of V24JQ
NK T cells in gingival tissue is a characteristic feature in both
periodontitis lesions and gingivitis lesions.
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As with the previous reports, the dominant cell types were B cells and plasma cells. However, a significant number of T cells were also observed. The CD3+ cells formed clusters or were scattered beneath the pocket epithelium (data not shown).
V24+ cells and CD1d+
cells were found in all of the tissues examined. The proportion of
V24+ cells to CD3+ cells
in periodontitis tissue was the same as that of peripheral blood, which
had been determined in a preliminary experiment in four out of seven
specimens. In three cases, a very high proportion of
V24+ cells was observed (Table 2)
. However, we could not find any
relationship between the proportion of V24+
cells and clinical condition. Although the specificity of the antibody
is not for the invariant V24JQ but for the variable V24 chain,
it is possible that these high proportions of
V24+ cells reflect the accumulation of NK T
cell population.
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24+ cells and CD1d+
cells were in close proximity with direct cell-cell contact sometimes
being observed. In most cases however, V24+
cells and CD1d+ cells were stained separately
(Figure 3, A–D)
.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study, we used SSCP methodology to analyze the invariant
V24JQ TCR within the V24 population. Most recently,
Illés and colleagues32
also applied the SSCP method
and demonstrated a great reduction of V24JQ NK T cells in the
peripheral blood of multiple sclerosis patients. We have used this
method previously to analyze the Vß repertoire of infiltrating T
cells in periodontitis lesion.33,34
It has been reported
that PCR-SSCP analysis can detect an accumulation of T cell clonotypes
in heterogeneous populations at a frequency of one in several
thousands, which is more sensitive than limiting dilution analysis
previously used to estimate the frequency of antigen-specific T cell
populations.35
If there is an autoimmune aspect to periodontitis, it follows that a
reduction in NK T cells might be involved in an elevated humoral immune
response to self hsp60 as well as periodontopathic bacterial GroEL.
However, it is of note that the results did not support this concept.
In the present study, we clearly demonstrated that the T cells bearing
the invariant V24JQ TCR are the dominant clone within the
V24+ population in periodontitis tissues,
which is considered to be the progressive lesion and less dominant in
gingivitis tissues, a possible stable lesion. Although one or two
additional faint bands were detected in some samples, there was no
difficulty in identifying the band as the invariant TCR in a given
sample by comparison with the positive control. The additional bands
appeared at the same position across the samples of periodontitis
tissues (Figure 1D
, bottom). As these bands were detected by the
JQ-specific probe, they are also considered to be the invariant TCR.
Interestingly, Kent and colleagues36
examined 126 T cell
clones bearing the invariant and variant V24JQ CDR3 region and
demonstrated that 15 clones possessed no N-region diversity, but bore
either a nucleotide sequence that resulted in an amino acid
substitution at the C-terminal amino acid in the V24 segment or the
first amino acid in the JQ segment. These nucleotide substitutions
may also have occurred in the patients we examined. However, direct
sequence of the DNA extracted from these bands is required to prove the
band in fact represents the invariant V24JQ TCR.
To the best of our knowledge, this is the first study to show
V24JQ NK T cells in bacterial infection-related chronic
inflammatory lesions. Although the role of NK T cells in chronic
inflammatory periodontal disease is not known, considering the function
of NK T cells as regulators of autoimmune responses, they may play a
role in controlling the tissue destruction mediated by autoreactive T
cells and B cells. In addition to elevated humoral immune response to
self-hsp60, we found that hsp60-reactive T cells accumulated in
periodontitis lesions (Yamazaki K, Ohsawa Y, Tabeta K, Ito H, Ueki K,
Yoshie H, Seymour GJ, manuscript in preparation). Therefore, the high
proportion of the invariant V24JQ T cells in periodontitis
tissues that is supposed to be a progressive lesion and in stable
gingivitis tissues may be explained by the idea that NK T cells
accumulate to control autoimmune response in each lesion by
differential functions. Alternatively, because the NK T cells have the
capacity to secrete rapidly both interleukin-4 (IL-4) and
interferon-
(IFN-) without priming but become polarized for the
production of IL-4 after stimulation13,37
they may
regulate the Th1/Th2 balance of CD4+ T helper
cells in the lesion. In this regard, it has been reported that both
Th1-type38
and Th2-type4
responses are
predominant in the periodontitis lesion suggesting that the activation
stage of NK T cell may explain these contradictory reports. In one case
of controls, the invariant V24JQ TCR was higher in gingival
tissue than in peripheral blood. Although the underlying mechanism is
not known, this may be indicative of the conversion from a stable
lesion to a progressive lesion.1
Although the proportion
of invariant V24JQ TCR was statistically higher in periodontitis
tissues compared with gingivitis tissues, they were still present in
the majority of gingivitis tissues and the proportion of V24JQ
TCR within V24+ cells was relatively similar
between periodontitis and gingivitis. As the T cells in the gingivitis
lesion and the periodontitis lesion are phenotypically
similar39
but functionally different,4
it
would be reasonable to consider that the cytokine profile by NK T cells
can be different in two distinct disease entities.
In the immunohistochemical study, we could identify
V24+ cells in periodontitis tissues. The
antibody used has a specificity for variable 24 chain not for
rearranged V24JQ. Therefore, the positive cells may include not
only NK T cells but also other V24+ cells. The
proportion of V24+ cells to
CD3+ cells was variable from 0.25 to 4.5%. This
wide variation may reflect different disease activity of the lesions
although the clinical profiles are similar. It is likely that different
T cell subsets predominate at different stages of
disease.40
In vitro studies demonstrated that NK T cells
specifically recognize glycolipid -galactosylceramide and its
synthetic homologue and that this recognition requires expression of
the MHC class I-like molecule CD1d.13,37,41-44
In
periodontitis lesions, morphologically distinct cell types expressed
CD1d antigen. Some of these cells seemed to interact with
V24+ cells. However, the ligand for the human
NK T cells has not been fully elucidated. Although it has been shown
that the reactivity of mouse V14+ NK T cells
for CD1d is greatly augmented by the addition of the glycosphingolipid
-galactosylceramide antigens41,43
the vast majority of
glycosphingolipids in mammalian cells have a ß rather than
linkage at the 1 position of the hexose to the sphingosine base.
Phytosphingolipids with an -linkage of the sugar are not known to be
abundant in microorganisms.45
Therefore, it remains to be
determined whether -galactosylceramide or some other
compound(s) is the natural ligand(s) responsible for NK T cell
activation. Detection of antigens being capable of binding to CD1d and
stimulating NK T cells in periodontopathic bacteria would be of
particular interest.
In summary, we demonstrated an elevation of V24JQ NK T cells in
the gingival lesion of periodontitis patients and to a lesser extent in
that of gingivitis patients as compared with peripheral blood of either
periodontitis patients or nondiseased controls. This finding is of
particular interest, because autoimmune mechanisms are thought to be
involved in the destructive periodontal disease process. Although the
reason for the elevated proportion of the NK T cells remains unclear,
it is postulated that NK T cells are recruited to down-regulate the
autoimmune response against self-components such as hsp60. At the same
time, they may control cellular and humoral immune responses by
producing different cytokines in gingivitis and periodontitis lesions,
respectively. To clarify these issues, further study is needed.
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Acknowledgements |
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Footnotes |
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Supported by grants from the Ministry of Education, Science, Sports and Culture of Japan (grants 10470458,10357020,and 10307054).
Accepted for publication January 5, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/ß+ cells: new clues to their origin, specificity, and function. J Exp Med 1995, 182:633-638/ß T cells demonstrates preferential use of several Vß genes and an invariant TCR chain. J Exp Med 1993, 178:1-1624-JQ/Vß11 T cell receptor is expressed in all individuals by clonally expanded CD4-8- T cells. J Exp Med 1994, 180:1171-117624+ CD4-CD8- T cells. J Exp Med 1997, 186:109-120ßTCR+CD4-CD8- T cell deficiency and IDDM in NOD/Lt mice. Diabetes 1997, 46:572-582[Abstract]
ßTCR+CD4-CD8- thymocytes. J Autoimmun 1997, 10:279-285[Medline]
/ß-T cell receptor (TCR)+CD4-CD8- (NKT) thymocytes prevent insulin-dependent diabetes mellitus in nonobese diabetic (NOD)/Lt mice by the influence of interleukin (IL)-4 and/or IL-10. J Exp Med 1998, 187:1047-105624JQ T cells in type 1 diabetes. Nature 1998, 391:177-181[Medline]
14+ NK T cells associated with disease development in autoimmune-prone mice. J Immunol 1996, 156:4035-4040[Abstract]
24JQ antigen receptor in patients with systemic sclerosis. J Exp Med 1995, 182:1163-1168 transcripts in brains of multiple sclerosis patients. Proc Natl Acad Sci USA 1990, 345:344-346
24JQ invariant TCR chain in the lesion of multiple sclerosis and chronic inflammatory demyelinating polyneuropathy. J Immunol 2000, 164:4375-438124JQ T cells with conservative a chain CDR3 region amino acid substitutions are restricted by CD1d. Hum Immunol 1999, 60:1080-1089[Medline]
14 NKT cells by glycosylceramides. Science 1997, 278:1626-1629This article has been cited by other articles:
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 Z. Illes, M. Shimamura, J. Newcombe, N. Oka, and T. Yamamura Accumulation of V{alpha}7.2-J{alpha}33 invariant T cells in human autoimmune inflammatory lesions in the nervous system Int. Immunol., February 1, 2004; 16(2): 223 - 230. [Abstract] [Full Text] [PDF]
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