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,
Departments of
* Pathology,
Pharmacology, and
Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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secretion by activated PP MC. Cell surface
marker analysis reveals that PP T cells consist of activated and memory
subpopulations compared with the predominantly naive T cells identified
in the PLN and mesenteric lymph nodes. Upon stimulation, only
CD45RBlowCD4+ PP T cells produce IL-10, whereas
secretion of IL-2, IL-4, and IFN- was not detected. Furthermore, PP
MC, but not PLN MC, stimulated through the TCR/CD3 complex suppress
proliferation of purified PLN T cells in vitro, evidence for a
regulatory function among PP lymphocytes. We conclude that PP favor
differentiation of an IL-10-producing, regulatory
CD45RBlowCD4+ T cell population and that
inhibition of T cell proliferation by activated PP MC may reflect
regulatory activity consistent with T regulatory
cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, induced by splenic dendritic
cells (7, 8, 9). Furthermore, PP dendritic cells themselves
secrete IL-10, an indication that, within the PP, T cells may be
exposed to Ag in the presence of IL-10 (9). Finally,
feeding soluble Ag to mice treated with Flt3 ligand, which expands
dendritic cell populations, induces a more profound state of
hyporesponsiveness compared with untreated control animals, suggesting
that in vivo PP dendritic cells play a central role in the induction of
tolerance following mucosal administration of Ag (10).
Tolerance established via repeated oral administration of low-dose Ag
leads to the development of CD4+ Th cells that
secrete type 2 (IL-4, IL-10) and type 3 (TGF-
) cytokines (11, 12). In addition to well-defined Th2 cells and the incompletely
characterized Th3 cells, each of which inhibits a systemic
Th1/delayed-type hypersensitivity response, two other immunoregulatory
CD4+ T cell subsets have recently been described.
Activated CD4+CD25+ T cells
inhibit both the induction and effector function of autoreactive T
cells in vitro through a cell-cell contact-dependent mechanism that
suppresses IL-2 production (13). In vivo,
CD4+CD25+ regulatory T
cells control intestinal inflammation induced in SCID mice by adoptive
transfer of CD45RBhighCD4+
T cells (14).
A second immunosuppressive CD4+ T cell subset,
designated T regulatory cells (Tr1), is generated in vitro via repeated
antigenic stimulation in the presence of IL-10. These nonproliferative
cells secrete predominantly IL-10 with modest IFN- production in
response to Ag-specific and allogeneic stimulation (15, 16). Abs to both IL-10 and TGF- abrogate inhibition of
responder T cells in vitro by activated Tr1 clones. As with
CD4+CD25+ regulatory T
cells, Ag-specific Tr1 cells also prevent colitis induced in SCID
recipients of
CD45RBhighCD4+ splenic T
cells, an indication that Tr1 cells regulate intestinal immune
responses (15).
The phenotype of T cells that migrate into the PP and are exposed to Ag
in vivo remains largely unexplored. We hypothesize that exposure to Ags
within the environment of the PP promotes the differentiation of T
cells with immunoregulatory functions. To investigate the functional
phenotype of PP T cells, mononuclear cells (MC) and isolated T cell
subsets were activated using stimulatory anti-CD3 Abs. Compared
with MC isolated from mesenteric lymph nodes (MLN) and peripheral lymph
nodes (PLN), PP MC exhibit vigorous proliferation and production of
IL-2 and IL-10. Furthermore, addition of exogenous IL-12 to stimulated
PP MC enhances both IFN- and IL-10 secretion, suggesting that IL-12
regulates PP T cell function. Cell surface marker analysis revealed
that PP contain activated and memory T cell populations compared with
the more naive T cells identified in the PLN and MLN. Isolation of PP T
cells subsets demonstrated that only
CD45RBlowCD4+ PP T cells
produce IL-10. Finally, PP MC activated through the TCR/CD3 complex
suppressed proliferation of purified PLN T cells, supporting our
hypothesis that the PP promotes differentiation of a regulatory T cell
subset with a phenotype consistent with Tr1 cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c mice (Taconic Farms, Germantown, NY) and DO11.10 TCR-transgenic mice (17), kindly provided by Dr. K. Murphy (Washington University, St. Louis, MO) were bred and maintained under specific pathogen-free housing in the Animal Resource Center at Case Western Reserve University (Cleveland, OH) in accordance with the guidelines of the Institutional Animal Use and Care Committee. Mice used in experiments were 10–15 wk of age.
Cell isolation
Small intestines were removed from pairs of mice and flushed with ice-cold calcium- and magnesium-free HBSS (BioWhittaker, Walkersville, MD). The PP were carefully excised with surgical scissors and kept in calcium- and magnesium-free HBSS until used. Excised PP, MLN, and PLN (superficial inguinal, popliteal, axillary, and lateral axillary nodes) were minced separately for 2 min and digested with collagenase (400 U/ml; Boehringer Mannheim, Indianapolis, IN) for 1 h at 37°C in RPMI 1640 containing 0.625 mM HEPES, 10% FCS, 250 U/ml penicillin, 250 µg/ml streptomycin, and 0.625 µg/ml fungizone (all from BioWhittaker). The digested tissue was filtered through a 100-µm nylon mesh (Falcon, Franklin Lakes, NJ) to yield a single cell suspension. Lymphocytes were enriched by density centrifugation, layering the single cell suspension over 30% Percoll (Amersham Pharmacia Biotech, Piscataway, NJ) and centrifuging for 20 min at 4°C. Purified lymphocytes in the resulting pellet were used for cell culture or flow cytometry.
Cell culture
MC from PP, MLN, or PLN were cultured at 37°C in a 5%
CO2 incubator in complete medium (RPMI 1640
supplemented with 10% FCS, 100 mM HEPES, 250 U/ml penicillin, 250
µg/ml streptomycin, 0.625 µg/ml fungizone, 2 mM
L-glutamine (all from BioWhittaker), 1 mM sodium pyruvate
(Life Technologies, Grand Island, NY), and 5 µM 2-ME (Sigma-Aldrich,
St. Louis, MO)). The following mAbs were added at culture initiation:
protein A affinity-purified anti-CD3 (2C11; hybridoma cell line
from American Type Culture Collection, Manassas, VA), anti-IL-4
(11B11), anti-IL-10 (JES5-2A5) (both from eBioscience, Palo Alto,
CA), anti-TGF- (9016.2), recombinant murine IL-12 (both from R&D
Systems, Minneapolis, MN), anti-IL-2R (TM-1), and
anti-IL-2R (TUGm2) (both from BD PharMingen, San Diego, CA).
Some cultures were stimulated with
OVA323–339 (Princeton Biomolecules,
Columbus, OH) at 0.67 µM or with anti-CD28 (37.51, BD
PharMingen).
ELISAs
MC were cultured at a density of 0.5 x
106 cells/ml in flat-bottom 48-well tissue
culture plates (Corning, Corning, NY) and cell culture supernatants
were removed 2 or 6 days after culture initiation and stored at
-70°C. Quantitative ELISAs were performed in 96-well ELISA plates
(Dynatech, Chantilly, VA) using paired mAbs according to the
manufacturers’ recommendations for IL-2, IL-4, IFN- (all from BD
PharMingen), and IL-10 (R&D Systems). For IL-12 (p40) ELISAs, the
following reagents were used: protein G purified anti-IL-12 mAbs
(C15.6; the kind gift of G. Trichieri; Wistar Institute, Philadelphia,
PA) to capture IL-12, biotinylated anti-IL-12 (C17.8; BD
PharMingen) to detect captured IL-12, and recombinant murine IL-12
standard (R&D Systems). Cytokine production was calculated using mean
values from quadruplicate cultures.
Proliferation assay
MC (1 x 105 cells/well) were cultured in 96-well U-bottom tissue culture plates (Falcon) for 72 h. To measure proliferation, [3H]thymidine (0.5 µCi/well; New England Nuclear, Boston, MA) was added for the final 24 h of incubation. The cells were harvested onto filter mats with a Tomtec cell harvester (Wallac, Gaithersburg, MD) and 3H incorporation into DNA determined using a scintillation counter (Wallac). Proliferation was calculated using mean values from triplicate cultures.
Flow cytometry
Single cell suspensions of MC from MLN, PLN, and PP were
analyzed for cell surface marker expression using flow cytometry with
reagents from BD PharMingen. For two-color flow cytometry, cells were
stained for 30 min at 4°C with previously optimized concentrations of
anti-CD3-FITC (17A2, rat IgG2b, 
) and one
of the following PE-conjugated Abs: anti-CD4 (H129.19, rat IgG2a,
), anti-CD45RB (C363.16.A, rat IgG2a,
), anti-CD69 (H1.2F3, Armenian hamster IgG, group1, 
), and
anti-CD62L/L-selectin (MEL-14, rat IgG2a, ). For three-color
flow cytometry, cells were stained as above using anti-CD4-FITC
(GK1.5, rat IgG2b, ), anti-CD69-PE, anti-CD28-PE (37.51,
Syrian hamster IgG, group 2, ), or anti-CD45RB-PE, and one of
the following biotin-conjugated Abs followed by streptavidin-PerCP:
anti-CD62L/L-selectin (MEL-14, rat IgG2a, ) or
anti-CD25/IL-2R 
-chain p55 (7D4, rat IgM, ). Appropriate
isotype-matched control Abs were included in every experiment.
Nonspecific Ab binding was blocked with Fc Block (2.4G2; BD
PharMingen). Data were collected at the Case Western Reserve University
Cancer Center Core flow cytometry facility using an Epics XL machine
(Coulter Electronics, Hialeah, FL) and WinList software (Verity
Software House, Topsham, ME). Data analysis was performed on 20,000
events using WinMDI 2.8 (The Scripps Institute, La Jolla, CA).
Purification and culture of T cell subsets
PP MC were stained with anti-CD4-FITC and anti-CD45RB-PE or anti-CD69-PE. Subpopulations of CD4+ cells were generated by two-color sorting on an Epics Elite cytometer (Coulter Electronics). Sorted CD4+ subpopulations were cultured as described for PP MC above, with 50,000 cells/well in 96-well U-bottom tissue culture plates precoated with 5 µg/ml anti-CD3 Abs. The resulting supernatants, collected at 2 and 6 days, were used in quantitative ELISAs.
In vitro assay to assess T cell suppression
The responder population was CD45RBhighCD4+ T cells isolated from PLN of DO11.10 mice via two-color sorting as described above. These PLN T cells (1 x 105) were placed into a 12-well plate in the presence of irradiated splenocytes (4000 rad, 1 x 106 cells) obtained from BALB/c mice. These cells were cocultured with PLN or PP MC from BALB/c mice, prepared as described above, placed into transwell culture inserts (0.4 µm; Corning, Acton, MA). After 48 h, the transwell was removed and the responding T cells in the lower chamber were resuspended and transferred to three wells in a 96-well plate. The responding T cells were pulsed with 0.5 µCi of [3H]thymidine and cultured for an additional 24 h, after which proliferation was measured.
Statistical analysis
Values are reported as means ± SEM. To test the significance of differences between two means, the Mann-Whitney U test was used. One-way ANOVA was used to compare among PP, MLN, and PLN responses (Prism; GraphPad, San Diego, CA). Differences were considered statistically significant when p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We propose that preferential differentiation of T cells toward
regulatory subsets occurs within the PP, which predicts that activated
PP T exhibit a response distinct from that of MLN and PLN lymphocytes.
PP MC stimulated through CD3 exhibited significantly greater
proliferation (p < 0.05) and IL-2 production
(p < 0.01) compared with MLN and PLN responses
(Fig. 1
). Neither proliferation nor IL-2
secretion distinguished MLN from PLN cells. Only 33% of PP cells are
CD3+, compared with >65% in the MLN and PLN
(data not shown); therefore, the increased IL-2 production and
proliferation after stimulation indicates that PP T cells are a primed
population.
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and IL-12 production by PP compared with PLN MC
PP cells may also consist of polarized T cell subsets that
preferentially secrete IFN- or IL-4. PP MC stimulated with
anti-CD3 Abs produced 11-fold less IFN- compared with cultures
from PLN (p < 0.01; Fig. 2); MLN IFN- secretion was similarly
reduced (p < 0.01). IL-4 production was
minimal in each of the stimulated lymphocyte populations tested. To
further characterize polarizing influences upon T cell differentiation
within the PP, IL-12 was measured. IL-12 secretion was not detected
from PP MC in the presence or absence of stimulation. However,
unstimulated cultures of MLN and PLN MC produced modest quantities of
IL-12. Stimulation led to a 3-fold induction of IL-12 by PLN
(p < 0.05) but not MLN MC. The vigorous
secretion of both IFN- and IL-12 by PLN MC distinguishes them from
MLN lymphocytes and suggests a proinflammatory cytokine polarization
for PLN T cells that is not observed in PP or MLN responses.
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To test our hypothesis that PP promote differentiation of a
regulatory T cell population, we measured production of IL-10.
Stimulated PP cells produced 2-fold more IL-10 than cultures from PLN
and MLN (p < 0.05; Fig. 3). As with proliferation and IL-2
production, IL-10 synthesis does not distinguish MLN from PLN. Elevated
IL-10 secretion by PP MC stimulated through CD3 supports our proposal
that PP favor differentiation of regulatory T cells.
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PP MC proliferate vigorously and secrete relatively high amounts
of IL-2 and IL-10 upon stimulation through the TCR/CD3 complex. Thus,
PP T cells represent a different phenotypic population, potentially
identifiable by cell surface molecules. Expression of proteins
differentiating between naive and memory cells was evaluated for
unstimulated CD3+ lymphocytes isolated from PP,
MLN, and PLN. Surface expression of CD4 was identical, indicating that
the distribution of the T cell population is similar between mucosal
and peripheral immune tissue (Fig. 4).
Among CD3+ PP cells, only 17% expressed
CD62L/L-selectin, greatly reduced compared with the 85%
CD62L+CD3+ cells isolated
from MLN and PLN. Consistent with these findings, the proportion of
CD45RBlow T cells was considerably greater in PP
(32%) compared with both MLN and PLN (18%), indicating that PP are
enriched for memory T cells. In addition, a greater percentage of
unstimulated T cells in the PP (48%) expressed CD69 compared with 13
and 10% CD69+ T cells in the MLN and PLN,
respectively. The percentage of CD4+ T cells
expressing CD25 was low and similar among all three tissues (11–13%).
Similarly, CD28 expression, which was at least 65% on the T cell
populations examined, varied little among tissues. MLN T cells could
not be distinguished from PLN T cells on the basis of cell surface
marker expression. In contrast to the naive populations within both
lymph nodes, a higher percentage of PP T cells displayed a memory and
activated phenotype.
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). For CD62L+ T
cells, expression of CD45RB and CD69 was consistent among the lymphoid
tissues examined.
Specifically, CD4+CD62L+
T cells obtained from PP, MLN, and PLN were >92%
CD45RBint/high while <6% were
CD69+. However, among
CD4+CD62L- T cells,
expression of CD45RB and CD69 was heterogeneous, with the overall
pattern reflecting the preponderance of activated and memory T cells
among PP lymphocytes observed in Fig. 4
. For example, among PP T cells,
20% were CD45RBlow and
CD62L-, compared with <8% for MLN and PLN
cells, further indication that a higher percentage of memory cells
resides in the PP. Moreover, a greater proportion of PP
CD4+ T cells were
CD69+CD62L- (25%),
compared with MLN and PLN cells (9 and 11%, respectively). Together
these results confirm that the PP T cell population is principally
composed of cells previously exposed to Ag, especially compared with
PLN and MLN lymphocytes. In addition, these findings demonstrate that,
in all lymphoid tissue examined, loss of CD62L expression is not
coordinately associated with a switch from a
CD45RBhigh to a CD45RBlow
phenotype.
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and IL-10 secretion from
stimulated PP MC
Detection of a mature T cell population suggests that other
factors, beyond IL-10 secretion, may contribute to the functional
phenotype of PP T cells. Investigations into immune regulation to Ags
in the intestinal lumen have suggested that TGF- may be important to
tolerogenic T cell function (11). Furthermore, IL-4
promotes T cell production of IL-10 (18). To test the
impact of the cytokine milieu upon their response to activation, PP MC
were cultured as described in Fig. 1 with the addition of blocking Abs
to IL-4, IL-10, and TGF-. The addition of anti-cytokine Abs did
not change the response of PP MC to activation through the TCR/CD3
complex (Table I). Specifically, IL-10
production was not contingent upon the presence of IL-4 in culture.
These data suggest that the functional response of these mature PP
cells is already established and is not dependent upon continuous
modulation by their immediate environment.
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and
undetectable IL-12, further evidence that the PP maintains an
immunoregulatory environment. However, the presence of inflammatory
mediators may change the response of PP T cells to activation. For
example, in human memory T cells, IL-12 enhances IL-10 production
(19, 20). To test this in murine systems, PP MC were
stimulated through the TCR/CD3 complex in the presence and absence of
IL-12. In the presence of IL-12, CD3-activated PP MC produced 8-fold
more IFN- and 2-fold more IL-10 compared with CD3 alone
(p < 0.05) (Fig. 6). By enhancing both IFN- and IL-10
production, IL-12 may activate the regulatory function of
IL-10-secreting PP cells.
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To identify the cellular source of IL-10 in our system,
subpopulations of PP T cells were isolated. PP MC were separated into
CD45RBhighCD4+ and
CD45RBlowCD4+
subpopulations via fluorescence-activated cell sorting and stimulated
with plate-bound anti-CD3 Abs. The resulting supernatants were
analyzed for IL-2, IL-4, IFN-, and IL-10 production. Notably, only
CD45RBlowCD4+ cells
activated through the TCR/CD3 complex produced striking quantities of
IL-10 (Fig. 7A). In contrast,
cytokine production was not detected from stimulated
CD45RBhighCD4+cells (Fig. 7A) or from unstimulated cells of either phenotype (data not
shown). Proliferation by the
CD45RBhighCD4+ PP T cell
population was 2-fold greater than that of
CD45RBlow cells (Fig. 7B).
Costimulation through CD28 in the presence of anti-CD3 Abs induced
a 6-fold increase in proliferation by both the naive and memory T
cells. CD28 costimulation enhanced the production of IL-2 by
CD45RBhighCD4+ PP T cells
to levels similar to those observed for PP MC stimulated through CD3
and CD28 (data not shown). Furthermore, the addition of anti-IL-2R
blocking Abs to cultures activated through CD3 reduced proliferation in
both the naive and memory PP T cell subsets by >50%, suggesting that
proliferation is IL-2 dependent. Finally, costimulation through CD28
also enhanced IL-10 production by CD45RBlow, but
not CD45RBhigh, CD4+ PP T
cells (Fig. 7C). Proliferation and cytokine production by
CD4+ PP T cells sorted into
CD69+ and CD69- subsets
were similar (data not shown), indicating that CD45RB expression, not
the activation profile, identifies a distinct PP T cell population.
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Secretion of IL-10 by stimulated
CD45RBlowCD4+ T cells is
consistent with the phenotype of Tr1 cells generated in vitro
(15). Therefore, we investigated the regulatory function
of PP MC stimulated through the TCR/CD3 complex. The responding T cell
population, CD45RBhighCD4+
T cells isolated from PLN of DO11.10 (OVA-TCR) mice and therefore
responsive to OVA323–339, was cultured with
irradiated APCs. These cells were then cocultured with PP or PLN MC
placed into a transwell cell culture insert. Cultures were stimulated
with OVA323–339, specific only for the
responding T cells in the bottom chamber, and stimulatory anti-CD3
Abs, capable of activating T cells in both the upper and lower
chambers. After 2 days, the transwell was discarded and the
proliferative response of the responding T cells from the bottom
chamber was measured. Whether cultured alone or in the presence of PLN
MC, T cell proliferation was vigorous (Fig. 8). In contrast, T cell proliferation to
anti-CD3 alone, or with OVA peptide, was reduced by 80 and 85%,
respectively, by stimulated PPMC. Thus, PP MC, but not PLN MC,
activated through the TCR/CD3 pathway suppress T cell proliferation to
nonspecific and Ag-specific stimulation in vitro.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PP dendritic cells are distinct from those isolated from other
secondary immune tissue and may contribute to the development of
IL-10-secreting
CD45RBlowCD4+ T cells.
Dendritic cells residing in different tissues induce distinct immune
responses from T cells (7, 8, 23). For instance,
repetitive stimulation using immature human dendritic cells leads to
differentiation of nonproliferative, IL-10-producing T cells with the
ability to suppress proliferation of Th1 cells in vitro
(16). Murine splenic dendritic cells promote naive T cells
to secrete IL-2 and IFN-, while PP dendritic cells induce production
of IL-4, IL-6, and IL-10 (7, 9). Myeloid PP dendritic
cells (CD11b+CD8-)
populate the subepithelial dome, located in close proximity to the M
cells that transport Ag from the intestinal lumen. These myeloid PP
dendritic cells, when presenting specific Ags, induce naive splenic T
cells to secrete IL-4 and IL-10. Furthermore, the myeloid PP dendritic
cells themselves, upon stimulation with CD40 ligand trimer or
Staphylococcus aureus and IFN-, secrete IL-10
(5). Thus, T cells within PP exposed to Ag from the
intestinal lumen presented by myeloid PP dendritic cells may become
activated in the presence of IL-10. The subsequent differentiation of
PP T cells toward a regulatory T cell population is consistent with our
data, which show that
CD45RBlowCD4+ PP T cells
secrete IL-10 upon stimulation. Absence of IL-4 secretion by PP T
cells, despite previous reports that PP dendritic cells induce this Th2
cytokine in naive splenic T cells, may reflect differences in splenic
vs PP T cells. We conclude that after exposure to Ags derived from food
and commensal flora T cells isolated from PP may perform
immunoregulatory functions and mediate natural tolerance to those
Ags.
PP T cells manifest characteristics similar to those previously
described for regulatory T cell populations, most notably Tr1 cells
developed in vitro via repeated antigenic stimulation in the presence
of IL-10 (15). Tr1 cells are also a
CD45RBlowCD4+ population
that upon activation are nonproliferative but secrete generous
quantities of IL-10 and modest quantities of IFN-, and suppress
naive T cell proliferation in vitro (15). Similarly,
CD45RBlowCD4+ PP T cells,
upon stimulation via the TCR/CD3 complex, exhibit reduced proliferation
and secrete principally IL-10, but not IFN- or IL-4. Furthermore, PP
MC stimulated through CD3 suppress proliferation of naive T cells in
vitro via soluble mediators, demonstrating a striking parallel between
memory PP T cells that differentiate in vivo and the Tr1 cell generated
in vitro.
Inhibiting IL-4, IL-10, and TGF- in vitro did not appear to
affect the functional response of PP T cells, suggesting that the
effector function of these cells is established in vivo and is not
readily modulated. While unstimulated MLN and PLN MC secrete IL-12, PP
MC do not secrete this cytokine spontaneously or in response to
activation. However, IL-12, in conjunction with stimulation through the
TCR/CD3 complex, not only augments PP MC IFN- production but also
enhances IL-10 secretion, a demonstration that T cells in the PP
express a functional IL-12R. The function of IL-12 appears to extend
beyond regulation of IFN-; in the PP IL-12 also induces
IL-10-secreting cells. Our observation that exogenous IL-12 induces the
expression of IL-10 in murine lymph nodes, including the PP, is an
extension of earlier studies using isolated human blood cells
(19, 20). The induction of both a proinflammatory cytokine
(IFN-) and an immunosuppressive cytokine (IL-10) by IL-12 may
reflect a mechanism to regulate inflammatory processes within the
mucosal immune system.
In this report we propose that a CD45RBlowCD4+ T cell population generated in the murine PP contributes to immune regulation in the gut. Secretion of IL-10 in response to stimulation and their memory phenotype distinguishes PP T cells from those found in MLN and PLN. Furthermore, a functional assay demonstrates that PP MC stimulated through the TCR/CD3 complex suppress naive T cells in vitro. CD45RBlowCD4+ PP T cells may be a regulatory T cell subset, possibly a Tr1 cell, which mediates natural tolerance to Ag taken up from the lumen of the intestine.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Alan D. Levine, Department of Medicine, Case Western Reserve School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106-4952. E-mail address: alanlevine{at}po.cwru.edu
3 Abbreviations used in this paper: PP, Peyer’s patch; MLN, mesenteric lymph node; MC, mononuclear cell; PLN, peripheral lymph node; Tr1, T regulatory cell 1.
Received for publication October 25, 2001. Accepted for publication April 8, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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+, and double-negative Peyer’s patch dendritic cells. J. Immunol. 166:4884.This article has been cited by other articles:
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 A. L. Woo, L. A. Gildea, L. M. Tack, M. L. Miller, Z. Spicer, D. E. Millhorn, F. D. Finkelman, D. J. Hassett, and G. E. Shull In Vivo Evidence for Interferon-gamma -mediated Homeostatic Mechanisms in Small Intestine of the NHE3 Na+/H+ Exchanger Knockout Model of Congenital Diarrhea J. Biol. Chem., December 6, 2002; 277(50): 49036 - 49046. [Abstract] [Full Text] [PDF]
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