Department of Medicine, University of California at San Diego, La Jolla, California 92093
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ABSTRACT |
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T cells are located in the paracellular
space between epithelial cells. In the human colon and small intestine,
5-40% of intraepithelial lymphocytes (IEL) are
T
cells, and in mice an even greater proportion of IEL are
T
cells. The
T cell receptor repertoire in the human
intestine undergoes marked changes in V region gene usage and
junctional diversity during development from fetus to newborn to adult,
suggesting that
T cells may mediate qualitatively or
quantitatively different functions at various stages of development.
IEL have been shown to produce cytokines and growth factors and
to influence epithelial cell proliferation and differentiation, as well
as the mucosal development of immunoglobulin A B cells.
IEL also
manifest cytolytic activity. However, the ligands recognized by
intestinal
T cells and the role they play in intestinal immune
responses, in immune defense to enteric pathogens, and in the
pathogenesis of intestinal disease are thus far largely unknown.
celiac disease; development; intraepithelial lymphocytes; mucosa; T cell repertoire
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INTRODUCTION |
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THERE ARE TWO MAJOR lineages of T cells,
those bearing the T cell receptor (TCR) and those that express
the
TCR.
T cells develop in the thymus, where they
undergo positive and negative selection with respect to self major
histocompatibility complex (MHC) molecules and antigens before
populating peripheral lymphoid sites. The restriction elements and many
of the functional properties of
T cells are well characterized.
T cells that express CD8 or CD4 as coreceptors recognize
peptides bound within the peptide-binding groove of MHC class I or
class II molecules, respectively. Many of the effector functions of
T cells, which are important in the regulation of immune and
inflammatory responses, are mediated by cytokines secreted by those
cells. CD8
T cells can also lyse target cells that express
foreign proteins (e.g., viral proteins) in the class I peptide-binding
groove. The majority of T cells in systemic and mucosal lymphoid
tissues are
T cells.
A second lineage of T cells expresses the TCR. This intriguing T
cell population is overrepresented in the intestine.
T cells
make up ~50% of intraepithelial lymphocytes (IEL) in the intestinal
mucosa of mice, 5-15% of human small intestinal IEL, and as much
as 40% of IEL in human colon, although they represent only a minor
fraction of T cells in most peripheral lymphoid tissues (<5%) (8,
11). Most intestinal
T cells are located in the paracellular
space between epithelial cells, on the luminal side of the
basement membrane, rather than in the underlying lamina propria.
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ONTOGENY OF INTESTINAL ![]() ![]() |
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T cell development is tightly regulated within the thymus. In
contrast, studies suggest that intestinal
T cells in mice and
humans can develop extrathymically as well as in the thymus. Thus, by 6 wk of gestation, T cells that express the
-receptor are found in
human fetal liver but are not yet detected in human fetal thymus (24).
In addition,
T cells are present in the intestine of
congenitally athymic mice (i.e., nude mice) and in thymectomized mice
reconstituted with fetal liver (1). Also consistent with extrathymic
development, intestinal
T cells in mice were shown to express
1) recombination-activating gene-1, which is essential for TCR gene rearrangement;
2) a homodimeric
form of CD8,
rather than the
heterodimer of CD8 found on most T cells
undergoing thymic development; and
3) the Fc
RI
chain
as a novel component of the TCR-associated CD3 complex (13, 15). The
intestinal epithelium may play a role in mucosal
T cell
development analogous to the role the thymic epithelium plays in
intrathymic T cell development (13). However, data also suggest the
thymus can indirectly contribute to the extrathymic development of
T cells (23). To the extent that
IEL undergo extrathymic
development, they may recognize a different array of antigens than
those recognized by T cells that undergo thymic selection, including
self antigens (i.e., the potential for autoimmunity).
Several characteristic changes that take place in the intestinal
T cell repertoire during ontogeny have been described (18). Diversity
of
- and
-chains of the
TCR is determined by combinatorial
joining of several gene segments (i.e., V, D, and J segments in TCR
genes; V and J segments in TCR
-chains), as well as by nucleotide
additions and deletions that occur at the junctions of those gene
segments. One can categorize the repertoire of
T cells in the
intestinal tract and at other anatomic sites on the basis of the array
of V gene segments used by the TCR and by nucleotide/amino acid
sequence diversity at the TCR junctional regions (also termed CDR3) (6,
16). Compared with
T cells,
T cells use a small number of
different V genes. Moreover, the use of different V genes by
T
cells in different anatomic sites is relatively compartmentalized. For
example, most
T cells in the skin, tongue, and female genital
tract of mice use a single V
and a single V
gene. Those
TCR also lack junctional diversity, suggesting they recognize a
monomorphic ligand. In contrast,
T cells in the human and murine
intestine use several different V
genes. In the normal adult human
intestine, expression of a single V
gene, DV1, is predominant (6).
Nonetheless, in some individuals, other V
genes can form a
substantial fraction of the repertoire. DV2 expression in particular is
prevalent, whereas DV3 is less so (16). Of note, the human TCR
locus maps within the TCR
locus, and in some individuals TCR
-receptors have been shown to use several different V
genes (16).
In contrast to the human intestinal mucosa, the predominant V
gene
used by circulating
T cells is DV2, and DV1-expressing cells are
only a minor component of circulating
T cells (6).
The TCR has the potential for extensive diversity within the
junctional region, and it is the junctional region that is thought to
be important for TCR ligand binding. Molecular analysis of
TCR
junctional regions has focused mainly on the TCR
-chain, since TCR
genes, unlike TCR
genes, are expressed exclusively in
T
cells. Paralleling their potential for extensive diversity, the TCR
genes expressed in the adult human intestine contain highly complex
junctional regions (6, 16). Thus it was perhaps surprising when
molecular analysis of the expressed TCR
genes in the intestine of
individual adults revealed that the TCR
repertoire in the intestine
was highly restricted (i.e., oligoclonal), not diverse. In each
individual the repertoire consisted of a relatively limited number of
different TCR
transcripts, some of which were clonally dominant (6,
16). Moreover, oligoclonality was a general feature of the intestinal
TCR
T cell repertoire in adults, irrespective of V region usage (6,
16). Within individual subjects, identical TCR
transcripts were
expressed at multiple sites within the small intestine or colon, and no overlap was noted among the TCR
transcripts expressed in the intestinal tract of different adults (6, 16). Moreover, the TCR
repertoire in the small intestine or colon of each individual was
relatively constant when assessed over a 1- to 2-yr period (6, 16). The
above findings are consistent with a model in which
T cells are
selected, possibly by ligands in the intestinal tract, and undergo
clonal expansion (i.e., either in a mucosal or an extramucosal site)
before seeding to multiple different sites in the small intestine and
colon. Because the repertoire of TCR
transcripts in the intestinal
mucosa differs from that in the peripheral circulation, different
ligands and/or factors may drive the expansion of the
T
cells in those different locations.
The TCR repertoire in the adult human intestine differs markedly
from that in early and midterm fetuses (18). The repertoire in midterm
fetuses, in turn, differs from the repertoire in the early postnatal
period and during the first few years of life. During fetal intestinal
development, expression of the DV2 gene segment, and not DV1,
predominates. Moreover, TCR
transcripts in the intestinal mucosa of
midterm fetuses (i.e., ~20 wk gestation) have relatively simple
junctions (i.e., minimal N-region nucleotide additions) and lack the
extensive diversity that is characteristic of TCR
junctional
regions in adults (18). Furthermore, in striking contrast to adults,
identical TCR
transcripts can be present in the intestinal tract of
different fetuses. However, TCR
junctional regions in newborns are
as complex as those of adults (18). The TCR
repertoire is
polyclonal in the newborn and during the first few years of life (18).
Nonetheless, by the second decade of life the intestinal TCR
repertoire is oligoclonal and resembles that of older adults. These
marked changes in the TCR
repertoire during development from fetus
to adult suggest that
T cells may play different roles at
different stages of development. For example,
T cells that
express a diverse repertoire at birth might be important in host
mucosal defense early in life, when antigen-specific acquired mucosal
immune responses that are mediated by
T cells and the secretory
immunoglobulin A (IgA) system are not fully developed.
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INTESTINAL ![]() ![]() |
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There are, on average, 20-100 epithelial cells for every
IEL in the adult human intestine. This relatively sparse distribution of
IEL and the oligoclonal nature of the adult
repertoire must be taken into account when considering mucosal
T cell function.
Consistent with their location in the paracellular space between
intestinal epithelial cells (IEC), T cells initially were envisioned to be a first line of defense against mucosal pathogens. However, there are few data to support that notion, and the intestinal
T cell population appears to be similar in germ-free and
conventional mice, whereas
IEL are markedly influenced by the
microbial flora (2). Furthermore, in the adult human colon, the TCR
repertoire is oligoclonal and relatively stable over time,
despite a highly diverse enteric microbial flora. Nonetheless, the
possibility exists that
T cells in adult humans recognize a
limited array of antigens that are highly conserved among different
bacterial strains.
Alternatively, direct microbial infection of epithelial cells or other
causes of epithelial cell stress or damage might result in the
expression of molecules on the epithelial cell membrane that can
activate adjacent IEL. In the periphery,
T cells in mice
are known to play a role in host defense, primarily after infection
with a spectrum of intracellular microbial pathogens (e.g.,
Listeria,
Mycobacteria,
Plasmodia,
Toxoplasma), but few data are
available regarding the role of intestinal
IEL in host defense
against intraepithelial pathogens. Moreover, given the scattered
distribution of
T cells in the epithelium, it is possible that
T cells that are not directly adjacent to stressed, damaged, or
infected epithelial cells are activated at a distance from those cells,
either by mediators released from epithelial cells or by signals
conducted across the intercellular junctions between IEC. In this
regard, epithelial cells are known to engage in crosstalk with
IEL, since they produce stem cell factor (SCF) and interleukin-7
(IL-7), which signal IEL via c-kit ligand (i.e., the receptor for SCF) and IL-7R, respectively (9, 25,
28).
The nature of the ligands recognized by T cells is unknown thus
far. On the basis of both the greater length and marked variability in
length of the junctional regions of TCR
chains relative to other
TCR chains, it has been proposed that
T cells might recognize
cell surface ligands in a manner analogous to that of immunoglobulin
molecules (5a). Whether
T cells recognize MHC class I-like
molecules such as CD1d in humans (see Ref. 3) or MHC class Ib molecules
such as MICA (i.e., a class Ib molecule expressed almost exclusively on
IEC and whose promoter contains heat shock elements similar to HSP70
genes) is not yet known (7, 12).
The fact that IEL reside within a sea of epithelial cells
suggests that an individual
T cell might monitor a group of epithelial cells. Moreover, when activated,
IEL may signal multiple target cells in the adjacent and underlying mucosa. In this
regard,
IEL produce an array of mediators, including cytokines, that are usually associated with antigen-specific immune responses (e.g., interferon-
) as well as proinflammatory chemokines that are
essential components of host innate immunity (4, 29). These findings
suggest
T cells can provide important signals to adjacent
epithelial cells and/or immune and inflammatory cells. Furthermore,
T cells in mice produce growth factors, which may
promote epithelial cell growth or play a role in healing a damaged
epithelium (5). In addition,
IEL can mediate cytotoxic functions. Thus,
T cells can be activated to express Fas ligand and are known to have cytolytic activity for target cells in in vitro
lysis assays, suggesting they may play a role in deleting damaged IEC
(19, 27). Other studies in mice have reported the induction of natural
killer cell markers on
T cells from the gut and natural killer
activity of those cells in vitro (14).
Studies in mice lacking T cells (i.e.,
knockout mice)
have provided additional insights regarding
T cell function. Such studies suggest
T cells are important for the development of mucosal IgA B cells and that
T cells in the intestinal mucosa can play a role in epithelial cell differentiation (10, 22). Although
knockout mice manifest greater intestinal immunopathology after
Eimeria infection than controls (26),
it is not known whether the latter reflects
1) a direct effect of
T cells
on the parasite or parasite-infected cells,
2) the absence of an immunoregulatory role of
T cells on the remaining
T
cells, or 3) a secondary effect, in
that
knockout mice are also IgA deficient. Other studies in mice
depleted of
T cells suggest those cells may play a role in
regulating oral tolerance (21).
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Celiac disease is characterized by small intestinal mucosal damage and
nutrient malabsorption after the dietary ingestion of
prolamins in wheat, rye, and barley in genetically
susceptible individuals (20). This disease is unique among small
intestinal disorders in that these patients manifest a striking
increase in the proportion of relative to
T cells in the
intraepithelial region of the small intestinal mucosa; this is
recognized as one of the hallmarks of celiac disease (20). Moreover,
the proportion of
IEL relative to
IEL remains increased
even in celiac disease patients in remission, which suggests a
fundamental role for these cells in the pathogenesis of this disease.
Monozygotic twins concordant for celiac disease were shown to have
nonoverlapping intestinal TCR
repertoires, indicating that the
genetic factors that determine celiac disease susceptibility do not
appear to select for specific TCR
sequences or junctional region
amino acid motifs (17). Nonetheless, the role
T cells play in
the pathogenesis of celiac disease, whether protective of the mucosa or
damaging to it, is not known.
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SUMMARY |
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T cells represent an intriguing, but as yet somewhat mysterious,
component of the intestinal mucosal immune system. They are located
predominately in the paracellular space between epithelial cells and
are therefore ideally situated for crosstalk with IEC and other immune
and nonimmune populations of cells in the adjacent lamina propria.
During the first few decades of life, mucosal
T cells appear to
be selected by ligands and undergo clonal expansion and recirculation
before lodging throughout the small intestine and colon. In adults the
repertoire of receptors used by this cell population is markedly
restricted and unique in each individual, despite the potential for
extensive diversity seen in the newborn. This suggests
T cells
in the intestinal mucosa may play different roles in the fetus and
newborn compared with their roles later in life. The unique structural
and developmental characteristics of the
TCR, their largely
extrathymic differentiation, and the production of an array of
mediators, including those characteristic of host innate immune
responses, further suggest that these fascinating cells may bridge
innate and acquired mucosal immunity. Currently the function of these
cells, the nature of the ligands they recognize, and their role in
normal intestinal immunophysiology and disease represent key unsolved
issues in mucosal T cell biology.
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FOOTNOTES |
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* Third in a series of invited articles on Current Concepts in Mucosal Immunity.
Address reprint requests to Univ. of California, San Diego, Dept. of Medicine, 0623D, 9500 Gilman Dr., La Jolla, CA 92093-0623.
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