1 Medizinische Klinik II, Division of Gastroenterology, Johann Wolfgang Goethe-Universität, 60590 Frankfurt am Main; 2 Department of Biology II, Ludwig-Maximilians-Universität München, 80539 München; and 3 Medizinische Klinik I, Universitätsklinikum Benjamin Franklin, 12200 Berlin, Germany
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ABSTRACT |
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/
T cells
might play an important role in autoimmune conditions like inflammatory
bowel disease (IBD). In the present study, we characterized the T cell
receptor (TCR)-
repertoire by complementarity determining region 3 (CDR3) spectratyping in the inflamed and noninflamed mucosa and in the
peripheral blood of subjects with Crohn's disease and ulcerative
colitis. In contrast to previously published data about
/
T
cells, we rarely found oligoclonal expansions of
/
T cells
specific only for the inflamed mucosa. The same dominant
/
T cell
expansions were also present in the noninflamed colon. Furthermore, the
peripheral
/
TCR repertoire was oligoclonal but clearly distinct
from that in the inflamed intestine. Thus our results do not support a
role for antigen-specific
/
T cells in IBD, and dominant
/
T cells of the peripheral blood are not likely to be derived from the
inflamed gut. However, in several patients, the TCR-
-repertoire was
highly diversified, whereas in others we observed a loss of dominant
/
T cell clones when inflamed and noninflamed mucosa were
compared. In conclusion, those changes indicate that
/
T cells
might play an important role in a subset of patients with IBD.
gamma/delta mucosal immunology; Crohn's disease; ulcerative colitis
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INTRODUCTION |
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INFLAMMATORY BOWEL DISEASE (IBD) comprises at least two human diseases of unknown etiology: Crohn's disease (CD) and ulcerative colitis (UC) (5). CD is characterized by a transmural inflammation and by skip lesions with macroscopically normal intervening mucosa among disease areas. The preferred localization of the disease is the terminal ileum, but the disease may affect any part of the gastrointestinal tract. One hallmark of CD is the granuloma formation in mucosal lesions. In contrast, the inflammatory lesions in UC are confined to the epithelium and the mucosa of the colon. Evidence that the immune system plays a major part in the pathophysiology of both diseases (5) derives from the ability to suppress these diseases by immunosuppressive therapy and from genetically modified animals with altered regulation of the immune system that develop severe chronic intestinal inflammation (15, 41).
Initial cellular events that take place at the outset of IBD are poorly
understood. CD and UC resemble autoimmune diseases, and numerous
publications support the notion that T cell-mediated mechanisms may
play a pivotal role in the pathogenesis of the disease
(41). For example, there is an increased number of
activated Lamina propria lymphocytes in the inflamed mucosa
of patients with CD (7, 11). These mucosal T cells might
have lost the physiological hyporesponsiveness to enteric antigens
(14). An important role of T cells is also supported by
various animal models of IBD, showing that gut inflammation can be
induced and transferred by T cells (36, 38, 42). In
addition, normal microflora is necessary in the development of gut
inflammation in all animal models (15), indicating that
microbial antigens might activate autoreactive T cells. Thus T cells
that specifically accumulate in mucosal lesions may represent a primary
oligoclonal T cell response that triggers the onset of the disease.
Clonally expanded /
T cells were described in the inflamed
intestine of patients with CD and UC (9, 39, 43, 48, 49),
and similar expansions could be also found in the peripheral blood (44). Although many studies have suggested a pathogenic
role for
/
T cells, little work has addressed
/
T cells.
/
T cells are a minor T cell population in humans, and their
functions are still largely unknown (reviewed in Refs. 25 and 33). It was suggested that they play an important role in regulating the mucosal immune response and are key mediators of autoimmune diseases (26). Intraepithelial
/
T cells
are thought to produce keratinocyte growth factor, which suggests a
role in maintaining the integrity of the epithelium (3).
However, two recent studies (16, 47) suggest that
this might not be the case. We have previously shown that the human
small and large intestine of healthy adults is populated by clonally
expanded
/
T cells that are widely distributed (10, 28,
31). Furthermore, the human skin, which forms another large
surface to the external environment, is also composed of clonally
expanded
/
T cells (30). The nature of the ligands
recognized by
/
T cells has been, in part, elucidated and was
shown to be nonproteinic and of low molecular mass (25).
Furthermore antigen recognition can be immunoglobulin-like without the
time-consuming protein processing step of major histocompatibility
complex presentation (8). In addition,
/
T cells are
thought to respond to self antigens rather than to foreign antigens
(1, 22, 24).
Several studies support the notion that /
T cells play a key role
in the pathogenesis of IBD. Immunohistochemical studies (37) reported an increased number of
/
T cells in
the inflamed mucosa, although contradictory studies (6, 12,
53) were published as well. Furthermore,
/
T cells were
found to be frequent in T cell areas around lymphoid follicles and
epithelioid granulomas of CD (19), and clonal
/
T
cell expansions were described in the inflamed mucosa of patients with
CD (35). In addition, analysis of peripheral blood
lymphocytes revealed an increased percentage of
/
T cells
expressing the T cell receptor DV1 (TCRDV1) gene segment (6, 20,
51). In normal subjects, TCRDV2 is preferentially expressed by
peripheral
/
T cells (4), whereas intestinal
/
T cells express mainly TCRDV1 (13, 28).
TCRDV1 is also the dominant V region in the inflamed mucosa of patients with IBD (37, 51). Thus circulating TCRDV1-expressing
/
T cells might be derived from colonic
/
T cells leaving
the inflamed gut.
The significance of these findings in subjects with IBD is unclear,
because it is not known whether the same expanded /
T cell clones
are also present in the noninflamed intestinal tissue or the peripheral
blood. The finding of clonality within the inflamed colon does not
allow the conclusion that they are disease related, because healthy
subjects already express a highly oligoclonal TCR-
repertoire
(10, 28, 31). However, it might be possible to identify
autoreactive
/
T cell clones specifically expanded only within
IBD lesions by comparing them with
/
T cells from noninflamed
mucosa. Because T cells are generally activated and clonally expanded
through contact of their clonotypical TCR with an appropriate antigen,
we evaluated the complementarity determining region 3 (CDR3) regions of
TCR-
transcripts of mucosal and peripheral lymphocytes from patients
with CD and UC and compared them with those of inflammatory and healthy controls.
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METHODS |
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Sample collection and RT-PCR of TCR- transcripts.
Mucosal biopsies from inflamed and noninflamed mucosa, 2-3 mm in
size, were obtained by endoscopy from eight subjects with active CD
(F-M) and three subjects with active UC
(N-P). From subject L, we obtained
additional colonic biopsies 5 mo before the exacerbation of CD. From
subjects O and P, additional biopsies were
available from moderately inflamed mucosa located between the
noninflamed and highly inflamed colon. Biopsy specimens from IBD
subjects were categorized into those from inflamed and noninflamed intestine according to endoscopic appearances and histology of adjacent
samples. In addition, two inflammatory controls with diverticulitis
(Q and R) and five normal controls
(A-E) were included in the study. The distance between
noninflamed and inflamed specimens was ~10-20 cm. From four
healthy subjects (A-D), we (29) previously reported about the IgA and IgM variable heavy chain repertoire. The
distance between the two colonic biopsies of healthy adults were 1 m (A-C) or 10 cm (D and E).
Colonic biopsies were snap frozen immediately in liquid nitrogen.
Peripheral blood specimens were obtained at the time of endoscopy, and
peripheral blood mononuclear cells (PBMC) were isolated using a Ficoll
density gradient (28, 31). The age range of studied
subjects was 25-80 yr. All studies were approved by the University
of Frankfurt ethical committee on human subjects.
CDR3 spectratyping.
For analysis of CDR3 lengths, 2-3 µl of each PCR mixture was
added to formamide-containing loading buffer. PCR products were heat
denatured for 2 min at 95°C. PCR products were then size separated on
a 6% denaturing polyacrylamide gel and visualized by silver staining
(Silver Sequence DNA staining reagents) as recommended by the
manufacturer (Promega, Madison, WI). Bands were photographed by
exposing polyacrylamide gels for 8-15 s to an automatic
processor-compatible film (Silver Sequence). Demonstrating the
reproducibility of our method, the CDR3 profiles of the two corresponding PBMC samples (Fig. 1,
subjects A-D), which were analyzed
independently, were almost 100% identical.
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Direct sequencing of individual CDR3 length bands.
For direct sequencing of TCR- rearrangements, individual dominant
bands were excised from the gels and incubated at room temperature in
50 µl sterile distilled H2O, after which 5-µl aliquots were reamplified for 30-35 cycles using the same primers and PCR conditions described above. Double-stranded PCR products were directly
sequenced using the ABI automatic sequencer 310 and the ABI prism dye
terminator cycle sequencing ready reaction kit with AmpliTaq DNA
Polymerase, FS (Perkin-Elmer, Weiterstadt, Germany), according to the
conditions recommended by the manufacturer. For sequencing, the 3'
primer, which was used for the PCR amplification, was taken.
Sequence analysis and calculation of CDR3 lengths.
Nucleotide sequences were analyzed using PC/Gene and OMIGA software
(Oxford Molecular, Cambridge, UK). The lengths of the CDR3 regions of
translated TCR- chains were calculated as previously described
(28, 31, 45). This calculation is arbitrary, because the
exact borders of the CDR3 region are not defined and other groups use
different calculations. Here, CDR3 lengths were determined by the
number of amino acids between the conserved cysteine C, which is encoded near the 3' end of TCRDV regions, and the conserved GXG triplet, which is encoded by all TCRDJ regions, and
eight amino acids were subtracted (45) [e.g., the CDR3
region: CALGEQRNPLVNWTAQLFFGQG, which is 22 amino acids long, has a CDR3 length of 14 amino acids (22 - 8 = 14)].
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RESULTS |
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CDR3 length analysis of
TCR- transcripts from the colon and
PBMC of healthy subjects.
In a first set of experiments, we analyzed the TCR-
repertoire of
the colonic mucosa and PBMC of five healthy adults (subjects A-E). As shown in Fig. 1, the TCRDV1, -DV2,
and -DV3 repertoire in normal colon was oligoclonal, and highly similar
CDR3 profiles with identical dominant bands were present at distant
colon sites separated by a distance as far as 1 m. These findings
indicate that dominant
/
T cells are widely distributed
throughout the colon. However, we occasionally observed expanded
/
T cell clones, which were not present at both colon sites. For
example, colon biopsy I of subject A had
additional dominant TCRDV1 CDR3 length bands not present in the colon
of biopsy II (see arrows in Fig. 1). These minor variations
could not be assessed by our previous work where we characterized the
TCR-
repertoire by cloning and sequencing (10, 28, 31).
Dominant bands were also present in the peripheral blood. However, the
CDR3 profiles of the intestine and the peripheral blood were distinct
from each other, indicating that different
/
T cell subsets are
present in each organ.
CDR3 length analysis of TCR-
transcripts from the colon of subjects with CD.
TCRDV1- and -DV2-specific CDR3 spectratyping from noninflamed and
inflamed colonic mucosa of six subjects with active CD
(F-K) revealed oligoclonal
/
T cell expansions
(Fig. 2). Minor differences between the
CDR3 profiles of noninflamed and inflamed mucosa were within the range
seen in healthy subjects when biopsies from different colonic sites
were compared (Fig. 1). In contrast, the TCRDV3 profiles of inflamed
and noninflamed mucosa were different in all but one patient
(subject G). Because TCRDV3-specific PCR yields were very
low in subjects F, I, and J, it is
likely that TCRDV3 was rarely expressed. This is in accordance with
antibody studies in patients with IBD that demonstrated that TCRDV1 and
-DV2 are the major V regions expressed by
/
T cells in the
inflamed and noninflamed mucosa (37, 51). Thus it is
possible that TCRDV3 transcripts were just above the detection level,
which might have skewed the CDR3 profiles. This is supported by our
data from subject J, where we obtained different
TCRDV3 profiles from the two noninvolved biopsies. In each of
those cases, PCR was repeated with a 10-fold higher amount of cDNA that
did not result in stronger PCR products. However, in subjects
H and K, good PCR yields were obtained and additional
dominant bands were visible in the inflamed mucosa. Thus on the basis
of the small number of patients analyzed, we do not know whether those
differences are specific for Crohn's disease or are within the range
seen in our healthy controls.
|
Identical TCR- transcripts are present in
inflamed and noninflamed mucosa.
To confirm that identical clonal expansions were present in inflamed
and noninflamed tissue, dominant bands of identical CDR3 length from
TCRDV1, -DV2, and -DV3 transcripts were isolated from the gels,
reamplified, and directly sequenced. Sequence analysis confirmed
identical TCR-
rearrangements at both colon sites in 18 cases (Fig.
3). In subject K, different
TCRDV3 transcripts with a CDR3 length of nine were isolated from
involved and noninvolved mucosa.
|
There is no evidence for "gut-like" /
T
cells in the peripheral blood of subjects with Crohn's disease.
From four patients (F-I) PBMC samples were obtained at
the time of endoscopy. Similar to healthy controls (Fig. 1), most CDR3 profiles of peripheral TCR-
transcripts were also restricted and
clearly distinct from those of the intestine (Fig. 2). Thus dominant
/
T cells are unlikely to be derived from the inflamed mucosa as
suggested previously (6, 20, 51). From the PBMC sample of
subject H, the dominant TCRDV3 band with a CDR3 length of
nine was also analyzed, because it was identical in length with the
dominant bands of the colon. However, sequence analysis revealed that it contained a distinct TCR-
rearrangement (sequence H5200; Fig. 3), confirming that the repertoires of the blood and the
inflamed intestine are different. Similar data were obtained from the
patients with UC (see below).
The colonic and peripheral TCR- repertoire can be
highly diverse.
In two subjects with CD (L and M), we identified
highly polyclonal CDR3 profiles of mucosal TCRDV1 transcripts (Fig.
4). From one of them (L), we
were able to obtain tissue and PBMC during remission and at the onset
of active disease 5 mo later. However, there was no significant change
in the CDR3 profile over time and the repertoire remained polyclonal.
Thus the TCR-
repertoire can be very variable in CD, but we rarely
identified dominant clones expanded only within the inflamed intestine.
|
Distinct TCR- repertoires are present in the
highly inflamed colon of subjects with UC.
In subject N, the colonic CDR3 profile was polyclonal for
TCRDV1 and -DV2 and oligoclonal for TCRDV3 (Fig.
5). We do note that the noninflamed colon
contained clonal TCRDV1 expansions not visible in the polyclonal
repertoire of the inflamed colon. The CDR3 profiles of peripheral
TCRDV2 transcripts were polyclonal, whereas peripheral TCRDV1 and -DV3
repertoires were highly oligoclonal and distinct from the intestinal
TCR-
repertoire. In the second patient (O) we observed
significant changes between normal and diseased colon. The CDR3
profiles of TCRDV1, -DV2, and -DV3 transcripts from the
noninflamed and moderately inflamed tissue were highly oligoclonal and
almost identical. Sequence analysis of dominant bands confirmed
identical TCR-
transcripts at different colon sites (Fig.
6A). However, this typical
CDR3 pattern was lost in the highly inflamed areas and a polyclonal
repertoire predominated. Possibly this could reflect the influx of
peripheral
/
T cells in the inflamed colon, because the TCRDV1
and -DV2 repertoires of PBMC were highly polyclonal as well. In
contrast, there was a loss of dominant clones in the third,
patient P, when the TCRDV1, -DV2, and -DV3 repertoires of
highly inflamed and noninflamed mucosa were compared. Furthermore,
sequence analysis of dominant TCRDV3 bands with a CDR3 length of 16 demonstrated that different TCRDV3 rearrangements were present in the
inflamed and noninflamed colon (Fig. 6A).
|
|
Identical dominant TCR- rearrangements are
present in inflamed and noninflamed mucosa of patients with
diverticulitis.
We further studied the TCRDV1, -DV2, and -DV3 profiles of two
inflammatory controls (Q and R) suffering from
diverticulitis (Fig. 7). Similar to what
we observed in the subjects with CD, we did not see a significant
change in the CDR3 profiles of TCRDV1/transcripts between inflamed and
noninflamed mucosa, and sequence analysis confirmed identical TCRDV1
transcripts at both sites (Fig. 6B). The TCR-
repertoires of the peripheral blood and the intestine were distinct.
The PCR yield of colonic TCRDV3 transcripts of subject Q was
low, and we were unable to amplify any TCRDV3 transcripts from the
noninflamed mucosa.
|
Characteristics of mucosal TCR- transcripts from
subjects with CD, UC, and diverticulitis.
All sequences were highly complex, as shown by extensive trimming of
the gene segments and multiple N region additions (Figs. 3 and 6). An
overutilization of the TCRDJ3 gene segment was suggested before for
TCRDV1 and -DV3 transcripts of the inflamed colon of subjects with CD
(35). However, none of our TCRDV1 and -DV3 transcripts
contained the DJ3 gene segment and the vast majority used DJ1. DJ3 was
only found in conjunction with TCRDV2 transcripts. DJ3 is also
frequently used by TCRDV2 transcripts in healthy subjects (28). Translation into corresponding amino acid sequences
did not reveal any obvious motif shared among different subjects (Fig. 8).
|
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DISCUSSION |
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Previous studies proposed an important role for /
T
cells in the pathogenesis of IBD (6, 20, 51), and an
increased number of
/
T cells (19, 37) with clonal
expansions was reported (35) in the inflamed mucosa. It
was hypothesized that unidentified antigens, presumably from the
intestinal microflora, might activate autoreactive mucosal
/
T
cells that initiate a destructive immune response. Autoreactive
/
T cells were also thought to be responsible for other autoimmune
diseases like multiple sclerosis where several groups
(32, 50) identified oligoclonal expansions in brain
lesions. Thus the identification of clonally expanded
/
T cells in
the inflamed intestine of subjects with IBD, as suggested before for
/
T cells (9, 23, 39, 43, 48, 49), would support the
notion that autoreactive
/
T cells might damage the mucosa.
As shown herein, we rarely identified that /
T cell clones
exclusively expanded only in the inflamed mucosa, and highly similar
CDR3 profiles and identical TCR-
transcripts were present in the
inflamed and noninflamed mucosa of most patients. Because the TCR-
repertoire can also differ between two colonic sites of healthy
subjects, we do not know whether those expansions, which were
especially found within the TCRDV3 repertoires, are specific for IBD.
However, we observed significant changes, such as the diversification
of the TCR-
repertoire or the "loss" of dominant clones, in a
subset of patients. A diverse intestinal TCRDV2 repertoire was also
described by others in patients with CD. (34). Whereas the
diversification of the mucosal repertoire might have been caused by
peripheral
/
T cells infiltrating the inflamed mucosa, it is not
clear why dominant clones, which are present in the noninvolved mucosa,
are absent in the inflamed mucosa of other patients. Thus changes of
the TCR-
repertoire can be highly variable and are distinct from
those described for
/
T cells.
Lack of clonally expanded /
T cells, which are specific for
the inflamed mucosa, does not exclude the possibility that
/
T
cells play a significant role in the destructive nature of the immune
response. First,
/
T cells might be activated by stress-induced self antigens (22) that could lead into tissue damage. It
is possible that the
/
TCR repertoire in normal mucosa is already shaped by self antigens under physiological conditions, and
further activation through the same self antigens would only cause a
proliferation of local
/
T cells with no change of the TCR-
repertoire. This is supported by our observation that we could not see
any change in the repertoire between the inflamed and noninflamed
mucosa of subjects with diverticulitis. Second, mucosal
/
T cells might be just bystanders of an ongoing inflammation and
their response could be triggered by CD3-independent mechanisms or
inflammatory signals such as chemokines alone, which are secreted by
other immune cells (46). Third, there might be only a few
disease-specific autoreactive
/
T cells within the inflamed
mucosa that are very rare but control the vast majority of nonspecific
cells (52). Finally, the possibility remains that
pathogenic T cell clones are not restricted to inflamed areas but are
present throughout the intestine.
Several groups independently described an increase of
TCRDV1-expressing /
T cells in the peripheral blood of subjects
with active IBD. Because TCRDV1 is predominantly expressed not only in
healthy mucosa (13, 28, 40) but also in the diseased mucosa (37, 51), it was suggested that peripheral
/
T cells are likely to be derived from the inflamed intestine (6,
20, 51). However, this scenario is unlikely, because our data
demonstrate that
/
T cell clones, which predominate in the
inflamed intestine, are different from those that predominate in the
peripheral blood.
In summary, we have shown that there can be significant
differences between the TCR- repertoire of the inflamed and
noninflamed colon, indicating that
/
T cells play a significant
role in a subset of patients with IBD. The opposite findings, like the diversification of the TCR-
repertoire or the loss of dominant clones, might be explained by the hypothesis that CD and UC are not
just two diseases but are likely to consist of several different subgroups that all have a distinct pathophysiology (21).
In animal models, different al terations of the immune system
all resulted in a common final pathway: the inflamed intestine
(15). Because our findings are distinct from those
described for
/
T cells, it is possible that
/
T cells
might not damage the mucosa but have important secondary roles in IBD
like the downregulation of the inflammatory process or regeneration of
the damaged mucosa (3). This is supported by studies that
suggest that
/
T cells induce oral tolerance (26),
maintain T cell hyporesponsiveness of mucosal T cells (2,
18), and secrete cytokines promoting growth and differentiation
of epithelial cells (3, 17). In addition,
/
T cells
were shown to have a protective role in rat 2,4,6-trinitrobenzene
sulphonic acid colitis, because depletion caused increased mortality
(27).
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ACKNOWLEDGEMENTS |
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This work was supported by Grant Ho1521/2-2 from the Deutsche Forschungsgemeinschaft (to W. Holtmeier) and Grant Du193/2-4 (to R. Duchmann).
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FOOTNOTES |
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This work was presented, in part, as a poster during the Digestive Disease Week in New Orleans, LA, May 1998.
Address for reprint requests and other correspondence: W. Holtmeier, Medizinische Klinik II, Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany (E-mail: W.Holtmeier{at}em.uni-frankfurt.de).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published January 16, 2002;10.1152/ajpgi.00224.2001
Received 31 May 2001; accepted in final form 10 January 2002.
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