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Division of Gastroenterology and Center for Immunology, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We used the DO11.10 TCR transgenic adoptive transfer system to track the phenotype of Ag-specific CD4 T cells following Ag exposure. All donor mice were bred onto the RAG-2-deficient background and had few T cells expressing CD25. Peripheral tolerance was induced either by i.v. injection of peptide Ag or oral protein administration. Indeed, a subpopulation of CD4 T cells constitutively coexpressing CD25, phenotypically similar to immunoregulatory CD25+CD4 T cells described previously (2, 11, 12), emerged within the lymphoid tissues of tolerized animals. In contrast, these cells did not appear following immunization with peptide and adjuvant. An inverse correlation between the numbers of CD25+CD4 T cells and number of cell divisions following Ag exposure was noted. The greatest yield of CD25+CD4 T cells followed a low dose tolerance protocol, which may be analogous to dietary Ag exposure. These results suggest that peripheral induction of CD25+CD4 T cells in response toward innocuous environmental Ags may contribute to the pool of immunoregulatory CD25+CD4 T cells produced directly in the thymus in response to self Ags.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The DO11.10 TCR transgenic mice (13), extensively backcrossed (>15 generations) onto the BALB/c background, were crossed with RAG-2-deficient mice purchased from Taconic (Germantown, NY). All donor mice were RAG-2-deficient DO11.10 TCR transgenic confirmed by staining peripheral blood cells for presence of KJ1-26+CD4 T cells and absence of B cells. Donor mice were maintained on autoclaved food and water in a specific pathogen-free facility in microisolator cages with filtered air according to National Institutes of Health guidelines. RAG-2-deficient DO11.10 CD4 T cells were adoptively transferred (2.5–5 x 106 cells per mouse) by i.v. injection into unirradiated BALB/c mice, as previously described (14). In some of the experiments, donor cells were labeled with CFSE (Molecular Probes, Eugene, OR) before transfer, using a technique previously described (15).
Abs and staining reagents
The following Abs and secondary reagents used for flow cytometry
were purchased from BD PharMingen (San Diego, CA): CyChrome-labeled
anti-CD4, PerCP-labeled anti-CD4,
allophycocyanin-labeled anti-CD25, PE-labeled anti-CD25,
PE-labeled anti-IL-2, PE-labeled anti-IFN-
, PE-labeled
anti-IL-4, PE-labeled anti-IL-5, PE-labeled anti-CTLA-4,
and allophycocyanin-labeled streptavidin. The following Abs and
secondary reagents were purchased from Caltag (Burlingame, CA):
PE-labeled KJ1-26 and PE-labeled streptavidin. Biotin-labeled KJ1-26
was generously provided by M. K. Jenkins (University of Minnesota,
Minneapolis, MN). The following neutralizing Abs were used in the in
vitro blocking studies: anti-IL-10, clone JES5-2A5 (PharMingen),
and anti-TGF-
(R&D Systems, Minneapolis, MN).
Immunization and tolerance induction
A single i.v. injection of the OVA peptide 323–339, synthesized at Research Genetics (Huntsville, AL), at a dose of 5 µg per mouse, unless specified otherwise, was used to induce tolerance. LPS (25 µg), serotype Escherichia coli 026:B6 from Difco Laboratories (Detroit, MI), was mixed with the peptide and administered i.v. to induce priming.
Oral tolerance was induced by letting mice drink tap water containing OVA protein. Food and water were withheld from mice for 8 h, after which they were offered water containing OVA (Sigma, St. Louis, MO) at 25 mg/ml concentration for 18 h overnight. The amount of water consumed was measured and averaged 1 ml.
In vitro lymph node cell cultures
Suppressive properties of Ag-specific CD25+ T cells were tested using approaches of their depletion from or addition to in vitro cultures.
For the depletion approach, axillary, brachial, inguinal, and cervical lymph nodes were taken from untreated, primed, or tolerized mice (at least 8 days after initial Ag exposure). Lymph node cells were resuspended in 10 ml media and split into two halves. One half was stained with an irrelevant biotinylated rat mAb, and one with biotinylated anti-CD25 (7D4). Streptavidin magnetic beads (Dynal, Lake Success, NY) were then used to deplete Ab-bound cells according to the manufacturer’s instructions. About 90% depletion of CD25+ T cells was achieved in most experiments. Lymph node cells (3–5 x 106/ml) were then incubated in 24-well plates in enriched Eagle’s medium (EHAA) medium (Biofluids, Rockville, MD) supplemented with 10% FCS, 2 mM L-glutamine, 100 U/ml penicillin G, 100 µg/ml streptomycin, 20 µg/ml gentamicin, and 0.05 mM 2-ME at 37°C with or without OVA peptide at indicated concentrations, and supernatants were collected at different time points. The numbers of CD25+KJ1-26+CD4+ T cells and CD25-KJ1-26+CD4+ T cells put into each well were determined using flow cytometry.
Suppressive properties of CD25+ T cells were also
tested by their addition to cultures containing naive RAG-2-deficient
DO11.10 responder cells. CD25+ T cells from
normal BALB/c mice (endogenous CD25+ T cells), or
adoptively transferred and tolerized mice (endogenous and DO11.10
RAG-2-deficient CD25+ T cells), or naturally
occurring CD25+ DO11.10 cells from wild-type
transgenics were positively selected using magnetic streptavidin
microbeads (Miltenyi Biotec, Auburn, CA), according to the
manufacturer’s instructions. These were cultured in 24-well plates
with 50,000 RAG-2-deficient DO11.10 responder cells, 2.5 x
106 CD4-depleted BALB/c irradiated splenocytes as
APCs. Each well contained equal numbers (2.5 x
106) of endogenous CD25+ T
cells and differed only in the presence or absence of DO11.10
CD25+ T cells put in 1:1 ratio with the naive
DO11.10 responder cells. Some of the wells were treated with 10 µg/ml
anti-IL-10 and anti-TGF- Abs. IL-2 was measured in the 48-h
supernatants, as described below.
Direct comparison of suppressive properties of Ag-specific (DO11.10 RAG-2-deficient) CD25+ T cells and endogenous CD25+ T cells was done with the aid of physical cell sorting. RAG-2-deficient DO11.10 cells were dyed with CFSE before adoptive transfer and tolerance induction. CD25+ T cells positively selected with magnetic beads were separated into CFSE-high (DO11.10+ CD25+ T cells) and CFSE-negative fractions (DO11.10- CD25+ T cells) using FACSVantage high speed sorting. Different numbers of CD25+ T cells were cultured with 10,000 naive RAG-2-deficient DO11.10 responder cells and 1 x 106 CD4-depleted irradiated splenocytes APCs in the presence or absence of 5 µM OVA peptide in 96-well plates. IL-2 was measured in the 48-h supernatants, and proliferative response of the responder cells was done by direct counting using FACS because CD25+ DO11.10 cells could be distinguished by residual CFSE dye.
Measurement of IL-2 in the supernatants using flow cytometry
A total of 1 x 106 latex beads
(Interfacial Dynamics, Portland, OR) coated with anti-IL-2 capture
mAb JES6-1A12 (PharMingen) and blocked with medium containing 10% FCS
was incubated with culture supernatants for 2 h at 4°C. The
beads were then washed, incubated with biotin-labeled detection
anti-IL-2 mAb JES6-5H4 (PharMingen) for 1 h, washed again, and
incubated with PE-labeled streptavidin for 10 min. Geometric mean
fluorescence intensity of beads was then measured by flow cytometry and
plotted on a standard curve generated using media with known
concentrations of IL-2. This method had 
10-fold greater sensitivity
and lesser variability compared with a sandwich ELISA using the same Ab
pairs.
Measurement of IL-2 production in vivo in response to peptide Ag stimulation using flow cytometry
A modification of the method described previously (16) was used. One to two hours after mice were pulsed with 250 µg of the OVA Ag i.v., their lymph nodes or spleens were collected on ice. Single cell suspensions were Fc blocked and surface stained for CD4, CD25, and the DO11.10 transgenic TCR. Cells were then washed with PBS and fixed for 20 min with 2% formaldehyde. Cells were washed with PBS again and permeabilized with a buffer containing 0.3% saponin and 25% FCS. Intracellular staining was then done using PE-labeled anti-IL-2 mAb (PharMingen) for 30 min in the permeabilization buffer. Cells were then sequentially washed with a buffer containing 0.5% saponin and 2% FCS, PBS, and staining buffer (PBS, 2% FCS, 0.02% sodium azide). IL-2 production by individual cells was then measured using flow cytometry. KJ1-26-CD4+ T cells in the same tubes, as well as KJ1-26+CD4+ T cells from mice that did not receive the Ag pulse but were stained in parallel, served as negative controls. Surface staining for CD25 before permeabilization within the 1–2 h after Ag rechallenge ensured that intracellular CD25 induced by the Ag would not be detected.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The DO11.10 TCR transgenic adoptive transfer system
(14) was used to track the phenotype of Ag-specific
CD4+ T cells in vivo following peripheral Ag
exposure. It is well established that systemic, soluble Ag
administration results in establishment of peripheral immunologic
tolerance, but Ag administration accompanied by an adjuvant leads to
immunologic priming (17, 18, 19). The DO11.10 TCR transgenic T
cell adoptive transfer system was used previously to characterize the
fate of Ag-specific CD4 T cells following these two different types of
Ag exposure (14, 16, 20). Intravenous administration of
the OVA peptide 323–339 alone results in initial proliferation of
Ag-specific CD4 T cells until peak clonal expansion is reached on day
3, which is then followed by clonal deletion and functional
inactivation of the remaining Ag-specific CD4 T cells. The net result
of expansion and contraction of the Ag-specific CD4 T cell population
following a single wave of Ag in this model is a population that is
smaller than the starting one and also functionally hyporesponsive to
restimulation at the level of an average individual cell (14, 20). In contrast, while addition of LPS to the Ag does not
change the overall kinetics of the T cell response, the end result is
an expanded population of Ag-specific CD4 T cells that on restimulation
produce large amounts of IL-2 and gain ability to produce effector
cytokines such as IFN- (16, 20). The reported
phenotypic characteristics of immunoregulatory
CD25+CD4 T cells resemble some of the phenotypic
characteristics of CD4 T cells tolerized in vivo with i.v. peptide Ag.
Thus, CD25+CD4 T cells are unable to make IL-2 in
vitro and proliferate poorly following TCR stimulation. Therefore, we
wished to see whether a population of immunoregulatory
CD25+CD4 T cells emerges following peripheral
tolerance induction with i.v. peptide Ag.
About 5% of the DO11.10 CD4 T cells in the wild-type transgenic mice
coexpress CD25 (9, 11 , and data not shown). Existence of
these cells depends on expression of the second TCR resulting from
endogenous rearrangement of the TCR 
-chain. Therefore, to confine
our investigation of origin of CD25+CD4 T cells
exclusively to differentiation following peripheral Ag exposure, we
bred the donor mice onto the RAG-2-deficient background. Fewer than 1%
of the RAG-2-deficient DO11.10 CD4 T cells taken directly from the
intact transgenics stain positively for CD25 (9 , and data
not shown). Since the tolerant phenotype is established over the course
of 1 wk following systemic Ag exposure (21), we looked at
CD25 expression by DO11.10 T cells on day 8 or later following a single
i.v. dose of Ag. Indeed, a subpopulation of
CD25+CD4 T cells was noted to be present, but its
size was inversely correlated with the dose of the tolerizing peptide
(Fig. 1
). The inverse relationship
between Ag dose and CD25 expression by the DO11.10 T cells at this time
in the immune response argued against CD25 representing a mere
transient marker of activation. Furthermore, coadministration of an
adjuvant, LPS, along with the low dose peptide Ag (5 µg) also did not
lead to emergence of the Ag-specific
CD25+CD4+ T cell population
(Fig. 2). A more detailed kinetic
analysis showed that transient expression of CD25 was seen on all
Ag-specific T cells within 12 h of Ag administration regardless of
adjuvant presence. However, Ag-specific CD4 T cells expressing CD25 at
later time points were seen only following a tolerizing protocol. In
fact, there was an increase in the numbers of the
KJ1-26+CD4+ T cells
expressing CD25 between day 3 and day 8 following the tolerizing Ag
encounter (Fig. 2) despite the fall in the size of the total
KJ1-26+CD4+ T cell
population. Therefore, it is unlikely that the increased proportion of
CD25+ Ag-specific T cells seen following a
tolerance protocol can be explained merely by preferential death of the
CD25- Ag-specific T cells. The total number of
CD25+ Ag-specific T cells remained relatively
constant on days 16 and 23 following Ag exposure (data not shown).
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The number of cell divisions following Ag stimulation has been
shown to be a major variable controlling CD4+ T
cell differentiation (22). Thus, greater number of cell
divisions in the presence of appropriate cytokine signals correlates
with differentiation into polarized Th1 and Th2 cell populations and
ability to produce IFN- and IL-4, respectively (22).
Similarly, there is positive quantitative correlation between the
number of cell divisions and ability to make IL-2 upon recall
stimulation (23). The Ag dose dependence on the emergence
of CD25+CD4 T cells seen in our studies also
suggested a relationship to cell division history. To test this
hypothesis, we labeled the donor DO11.10 T cells with CFSE and compared
three different Ag exposure conditions: peptide alone at either low or
high dose, or low dose peptide with LPS. Four-color flow cytometry was
used to measure CD25 expression and cell division history of
Ag-specific CD4+ T cells (Fig. 3). Several conclusions can be drawn from
the analysis of these data. In all experimental conditions,
CD25+CD4 T cells were seen to have gone through
fewer cell divisions than CD25-CD4 T cells. Not
surprisingly, higher Ag dose on average resulted in more cell
divisions. Nevertheless, when the proportion of
CD25+ T cells was measured within subpopulations
of DO11.10 T cells that have undergone the same number of cell
divisions, both high and low dose i.v. tolerance protocols were
identical. Addition of adjuvant also led to more cell divisions for the
total DO11.10 T cell population. However, the proportion of
CD25+ T cells decreased more in the presence of
adjuvant than would be predicted if cell division history were the sole
variable controlling their induction.
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Oral tolerance is a form of systemic, Ag-specific immunologic
tolerance resulting from exposure to the Ag in the diet (24, 25). Many uncertainties remain about the mechanisms responsible
for oral tolerance. Clonal deletion, clonal anergy, and active
suppression have all been shown to participate in different
experimental systems (25, 26, 27, 28). Therefore, we tested the
possibility that CD25+CD4 T cells may arise
following peripheral tolerance induction by oral Ag administration.
Indeed, this proved to be the case (Fig. 4).
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25 mg OVA protein present in their
drinking water in a single 18-h period, and examined the phenotype of
adoptively transferred DO11.10 T cells at different time points after
the feeding. The kinetics of the response (data not shown) as well as
the extent of CFSE dilution suggests that the outcome of this oral
tolerance protocol is qualitatively similar to the one that follows low
dose peptide given i.v. In the oral tolerance protocol, there was
relatively more dilution of the CFSE dye in the DO11.10 T cells taken
from mesenteric lymph nodes as compared with sites more distant from
the gut: axillary, brachial, inguinal lymph nodes, and spleen
(Fig. 4
). Peripherally induced CD25+CD4+ T cells do not make IL-2 in vivo
One of the distinguishing features of the immunoregulatory
CD25+CD4 T cells described in the literature is
their inability to make IL-2 (11, 12). To evaluate
cytokine production by Ag-specific CD25+ and
CD25- CD4 T cells, we measured cytokine
production in response to Ag restimulation within individual cells
using flow cytometry. Ag-specific CD4 T cells were stimulated in vivo
using an i.v. pulse of peptide Ag, and cells were stained for cytokine
content directly ex vivo following fixation (16, 29). This assay takes advantage of the efficient and
synchronous Ag presentation in vivo within undisrupted lymphoid
tissues. Peak cytokine signal is seen at 1–2 h in Ag-experienced T
cells (29), with identical kinetics for both tolerized and
primed CD4 T cells (21). Peak production of IL-2 by naive
CD4 T cells occurs at 4–6 h (29). Only
CD25- DO11.10 T cells were seen making IL-2 in
vivo (Fig. 5). However, both
CD25+ and CD25- DO11.10 T
cells quickly up-regulated expression of CD69 in response to peptide
rechallenge (data not shown). Both oral and i.v. tolerance protocols
resulted in lesser ability of the DO11.10 T cells to make IL-2 upon
peptide Ag rechallenge compared with DO11.10 T cells that experienced
i.v. immunization with Ag and adjuvant. Staining for other cytokines,
including IFN-, IL-4, IL-5, and IL-10, showed no detectable signal
within either CD25+ or
CD25- cell populations (data not shown).
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Naturally occurring CD4 T cells constitutively expressing CD25 can
inhibit IL-2 production by CD25-CD4 T cells in
vitro (11, 12). This suppressive effect requires Ag
stimulation of the CD25+CD4 T cells, although the
Ag specificity may differ from the responding
CD25-CD4 T cell population. Therefore, we
compared IL-2 concentrations in supernatants of Ag-stimulated cultures
containing or lacking CD25+ T cells (Fig. 6). As shown above, only lymphoid tissues
of adoptively transferred mice tolerized with i.v. administered low Ag
dose contain significant numbers of DO11.10
CD25+CD4 T cells. In contrast, lymphoid tissues
of adoptively transferred mice that were not exposed to Ag, or received
Ag accompanied by LPS, contain only few DO11.10
CD25+CD4 T cells. All lymphoid tissues also
contain endogenous, polyclonal CD25+CD4 T cells
of unknown specificity. Single cell suspensions of lymph nodes taken
from adoptively transferred naive, primed, and tolerized mice were
split into equal volumes, stained with biotinylated anti-CD25 or
biotinylated isotype control Abs, depleted using streptavidin-coated
magnetic beads, and placed into culture with or without Ag. The number
of CD25- DO11.10 T cells was identical among the
undepleted and CD25 cell-depleted cultures. At 24 h of the in
vitro assay, IL-2 was detectable only if Ag was added. Increased
amounts of IL-2 were seen in all CD25-depleted cultures. However, IL-2
production increased the most in the tolerized group. Since only the
tolerized group contained significant numbers of OVA-specific
CD4+ T cells, this result is consistent with a
suppressive property of peripherally generated DO11.10
CD25+CD4+ T cells that is
dependent on Ag stimulation. Notably, somewhat improved IL-2 production
in CD25-depleted cultures was also seen in the naive and primed groups.
Therefore, it is possible that endogenous
CD25+CD4 T cells, which massively outnumber the
OVA-specific CD25+ T cells in these cultures,
suppress by an Ag-independent mechanism, respond to self Ags or other
Ags present in the medium, or merely consume IL-2.
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). Identical
numbers of naive DO11.10 responder cells were cultured with irradiated
APCs and positively selected CD25+ cells, which
either contained or did not contain a DO11.10+
CD25+ fraction. Endogenous
CD25+ cells lacking OVA-specific T cells were
obtained from the lymphoid tissues of normal BALB/c mice.
CD25+ cells containing the peripherally generated
OVA-specific fraction were obtained from adoptively transferred
tolerized mice. A third group contained endogenous
CD25+ T cells from unmanipulated BALB/c mice
mixed with naturally occurring CD25+ DO11.10 T
cells from intact wild-type DO11.10 transgenic mice. Thus, all cultures
contained equal numbers of endogenous polyclonal
CD25+ T cells, while the second and third groups
also contained equal numbers of either peripherally generated
CD25+ DO11.10 T cells or
CD25+ DO11.10 T cells from the wild-type
transgenic animals. OVA-specific CD25+ T cells
were present in a 1:1 ratio with the naive DO11.10 RAG-2-deficient
responder T cells. Both groups that contained Ag-specific
CD25+ T cells had significantly less IL-2 in the
supernatants, and suppressive potency of peripherally generated
Ag-specific CD25+ T cells was similar to that of
the naturally occurring DO11.10 CD25+ T cells
from wild-type transgenic animals. Reversal of suppression was not
achieved by neutralizing IL-10 and TGF- in the cultures, which is
consistent with the phenotype of immune regulation by
CD25+ T cells noted in the past that is different
from type 1 regulatory T cells or Th3 cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The goal of this study was to test the possibility that CD25+CD4 T cells with similar immunosuppressive phenotype can also be generated in the course of peripheral tolerance induction to a known Ag. Indeed, we found that to be possible, but only when Ag dose was low, such that cell cycle progression was limited. As anticipated, CD25 was promptly, but only transiently, expressed by Ag-specific CD4 T cells following Ag exposure. Late expression of CD25+ was seen only if Ag exposure was tolerogenic. The later expression of CD25 is unlikely to reflect acute activation because of the kinetically biphasic pattern of CD25 appearance, inverse correlation with Ag dose, and relative absence of CD25+CD4 T cells at these time points following priming with Ag and adjuvant. Phenotypically, peripherally generated Ag-specific CD25+CD4 T cells were indistinguishable in a number of assays from endogenous immunoregulatory CD25+CD4 T cells. They were unable to make any detectable IL-2, expressed high levels of CTLA-4 (data not shown), and suppressed IL-2 in the supernatants and proliferation of naive responder cells of the same Ag specificity in vitro cultures. The Ag-specific CD25+CD4 T cells were indistinguishable from Ag-specific CD25-CD4 T cells by cell size, which was equal to that of resting naive T cells, and levels of CD5 (data not shown). Clearly, our mechanistic analysis of suppression seen in in vitro cultures was limited in this study. Future studies will be done to determine whether the peripherally generated CD25+CD4 T cells mediate their suppression in vitro according to the same rules that were defined for the naturally occurring polyclonal CD25+CD4 T cells, dependent on direct contact between responder and suppressor T cells, dependent on Ag stimulation, independent of regulatory effects on the APCs, and Ag nonspecific (11, 31). Nevertheless, at the minimum, there are sufficient similarities in the phenotypes of these cells to raise the possibility that a subpopulation of the naturally occurring polyclonal immunoregulatory CD25+CD4 T cells may originate in the periphery rather than the thymus.
The data presented in this work are particularly relevant to the study of oral tolerance. Multiple uncertainties remain with regard to the mechanisms of oral tolerance as well as uptake and presentation of dietary Ags. Previous reports showed that orally administered Ag is encountered systemically within all lymphoid tissues (32), although detailed analyses of various feeding schedules are probably needed to further clarify this point. In this study, we attempted to compare an oral tolerance protocol with an i.v. peptide Ag protocol. Clearly, it is very difficult to estimate the amount of class II MHC/peptide complex seen by Ag-specific T cells following i.v. peptide Ag vs oral protein administration. Furthermore, the two routes of tolerance induction may differ in the types of APCs and costimulatory molecules provided. Nevertheless, the pattern of CFSE dilution in DO11.10 T cells suggested that our oral tolerance protocol is qualitatively similar to the low dose tolerance achieved with i.v. peptide Ag.
There is abundant literature suggesting that mechanisms of oral tolerance differ at different Ag doses (33). Relatively high Ag doses have been described to cause clonal deletion and anergy, while repeated administration of low Ag doses leads to development of suppressor T cells. Our results raise the possibility that CD25+CD4 T cells may indeed represent these suppressor cells and fit the Ag dose relationship noted in oral tolerance. If that were true, we would argue that peripheral induction of immunoregulatory T cells is not unique to oral tolerance. It may be that physiologic amounts of absorbed dietary Ags are typically in the low range; therefore, immunoregulatory mechanisms of tolerance may be more prominent in various oral tolerance protocols. Furthermore, the gastrointestinal tract along with the liver is a very efficient filter of LPS. Orally administered Ag delivered to distant lymph nodes is adjuvant free. In fact, commercial OVA protein given i.v. is relatively poor for tolerance induction. However, once LPS is extracted away, its potency is similar to that of synthesized peptide (A. Khoruts, unpublished observations). It is interesting to note that the percentage of CD25+CD4 Ag-specific T cells was greatest in the peripheral lymph nodes most distant from the gut, irrespective of cell division history. It is possible that some baseline exposure to bacterial products is present in the mesenteric lymph nodes, preventing optimal induction of the CD25+CD4 T cell subpopulation.
Ability to induce Ag-specific immunologic tolerance may be a strategy
to treat autoimmune diseases and transplant rejection. The profound
anergic phenotype of CD25+CD4 T cells and their
potential immunoregulatory properties make them a very desirable
subpopulation to be able to generate in the course of tolerance
induction. The results presented in this work suggest that Ag encounter
accompanied by minimal or no cell division are optimal conditions for
peripheral induction of these cells from naive precursors. A number of
clinically useful immunosuppressive agents (e.g., rapamycin, purine
metabolites, cyclophosphamide, etc.) inhibit cell division. In
addition, signals inhibitory to cell division are mediated through
multiple endogenous immunoregulatory molecules (e.g., CTLA-4, TGF-,
and IL-10). Future studies may test whether any of these agents can be
used as adjuncts for optimal induction of Ag-specific immunologic
tolerance. In addition, it will be clinically important to determine
whether differentiated effector or memory CD4 T cells can also be
driven to acquire an anergic and possibly immunoregulatory phenotype
in vivo.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Alexander Khoruts, Gastroenterology Division, Department of Medicine, Center for Immunology, University of Minnesota, MMC 334, BSBE Building, 312 Church Street Southeast, Minneapolis, MN 55455. E-mail address: khoru001{at}tc.umn.edu
Received for publication October 26, 2000. Accepted for publication April 26, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155:1151.[Abstract]
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Y. Burmeister, T. Lischke, A. C. Dahler, H. W. Mages, K.-P. Lam, A. J. Coyle, R. A. Kroczek, and A. Hutloff ICOS Controls the Pool Size of Effector-Memory and Regulatory T Cells J. Immunol., January 15, 2008; 180(2): 774 - 782. [Abstract] [Full Text] [PDF]
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C. Siewert, U. Lauer, S. Cording, T. Bopp, E. Schmitt, A. Hamann, and J. Huehn Experience-Driven Development: Effector/Memory-Like {alpha}E+Foxp3+ Regulatory T Cells Originate from Both Naive T Cells and Naturally Occurring Naive-Like Regulatory T Cells J. Immunol., January 1, 2008; 180(1): 146 - 155. [Abstract] [Full Text] [PDF]
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P. Chappert, M. Leboeuf, P. Rameau, D. Stockholm, R. Liblau, O. Danos, J. M. Davoust, and D.-A. Gross Antigen-Driven Interactions with Dendritic Cells and Expansion of Foxp3+ Regulatory T Cells Occur in the Absence of Inflammatory Signals J. Immunol., January 1, 2008; 180(1): 327 - 334. [Abstract] [Full Text] [PDF]
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A. M. Morton, B. McManus, P. Garside, A. McI. Mowat, and M. M. Harnett Inverse Rap1 and Phospho-ERK Expression Discriminate the Maintenance Phase of Tolerance and Priming of Antigen-Specific CD4+ T Cells In Vitro and In Vivo J. Immunol., December 15, 2007; 179(12): 8026 - 8034. [Abstract] [Full Text] [PDF]
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W. Hansen, A. M. Westendorf, S. Reinwald, D. Bruder, S. Deppenmeier, L. Groebe, M. Probst-Kepper, A. D. Gruber, R. Geffers, and J. Buer Chronic Antigen Stimulation In Vivo Induces a Distinct Population of Antigen-Specific Foxp3 CD25 Regulatory T Cells J. Immunol., December 15, 2007; 179(12): 8059 - 8068. [Abstract] [Full Text] [PDF]
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J. Wei, O. Duramad, O. A. Perng, S. L. Reiner, Y.-J. Liu, and F. X.-F. Qin Antagonistic nature of T helper 1/2 developmental programs in opposing peripheral induction of Foxp3+ regulatory T cells PNAS, November 13, 2007; 104(46): 18169 - 18174. [Abstract] [Full Text] [PDF]
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M. Dominguez-Villar, A. Munoz-Suano, B. Anaya-Baz, S. Aguilar, J. P. Novalbos, J. A. Giron, M. Rodriguez-Iglesias, and F. Garcia-Cozar Hepatitis C virus core protein up-regulates anergy-related genes and a new set of genes, which affects T cell homeostasis J. Leukoc. Biol., November 1, 2007; 82(5): 1301 - 1310. [Abstract] [Full Text] [PDF]
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J. A. Kapp, K. Honjo, L. M. Kapp, K. Goldsmith, and R. P. Bucy Antigen, in the Presence of TGF-beta, Induces Up-Regulation of FoxP3gfp+ in CD4+ TCR Transgenic T Cells That Mediate Linked Suppression of CD8+ T Cell Responses J. Immunol., August 15, 2007; 179(4): 2105 - 2114. [Abstract] [Full Text] [PDF]
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 J. L. Coombes, K. R.R. Siddiqui, C. V. Arancibia-Carcamo, J. Hall, C.-M. Sun, Y. Belkaid, and F. Powrie A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-{beta} and retinoic acid dependent mechanism J. Exp. Med., August 6, 2007; 204(8): 1757 - 1764. [Abstract] [Full Text] [PDF]
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T. So and M. Croft Cutting Edge: OX40 Inhibits TGF-beta- and Antigen-Driven Conversion of Naive CD4 T Cells into CD25+Foxp3+ T cells J. Immunol., August 1, 2007; 179(3): 1427 - 1430. [Abstract] [Full Text] [PDF]
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 A. Curti, S. Pandolfi, B. Valzasina, M. Aluigi, A. Isidori, E. Ferri, V. Salvestrini, G. Bonanno, S. Rutella, I. Durelli, et al. Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25- into CD25+ T regulatory cells Blood, April 1, 2007; 109(7): 2871 - 2877. [Abstract] [Full Text] [PDF]
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 D. A. MacKenzie, J. Schartner, J. Lin, A. Timmel, M. Jennens-Clough, C. G. Fathman, and C. M. Seroogy GRAIL Is Up-regulated in CD4+ CD25+ T Regulatory Cells and Is Sufficient for Conversion of T Cells to a Regulatory Phenotype J. Biol. Chem., March 30, 2007; 282(13): 9696 - 9702. [Abstract] [Full Text] [PDF]
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Y. Carrier, J. Yuan, V. K. Kuchroo, and H. L. Weiner Th3 Cells in Peripheral Tolerance. I. Induction of Foxp3-Positive Regulatory T Cells by Th3 Cells Derived from TGF-beta T Cell-Transgenic Mice J. Immunol., January 1, 2007; 178(1): 179 - 185. [Abstract] [Full Text] [PDF]
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G. M. Venturi, R. M. Conway, D. A. Steeber, and T. F. Tedder CD25+CD4+ Regulatory T Cell Migration Requires L-Selectin Expression: L-Selectin Transcriptional Regulation Balances Constitutive Receptor Turnover J. Immunol., January 1, 2007; 178(1): 291 - 300. [Abstract] [Full Text] [PDF]
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J.-B. Sun, S. Raghavan, A. Sjoling, S. Lundin, and J. Holmgren Oral Tolerance Induction with Antigen Conjugated to Cholera Toxin B Subunit Generates Both Foxp3+CD25+ and Foxp3-CD25- CD4+ Regulatory T Cells J. Immunol., December 1, 2006; 177(11): 7634 - 7644. [Abstract] [Full Text] [PDF]
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C. Gianfrani, M. K. Levings, C. Sartirana, G. Mazzarella, G. Barba, D. Zanzi, A. Camarca, G. Iaquinto, N. Giardullo, S. Auricchio, et al. Gliadin-Specific Type 1 Regulatory T Cells from the Intestinal Mucosa of Treated Celiac Patients Inhibit Pathogenic T Cells J. Immunol., September 15, 2006; 177(6): 4178 - 4186. [Abstract] [Full Text] [PDF]
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 A. Vojdani and J. Erde Regulatory T Cells, a Potent Immunoregulatory Target for CAM Researchers: Modulating Tumor Immunity, Autoimmunity and Alloreactive Immunity (III) Evid. Based Complement. Altern. Med., September 1, 2006; 3(3): 309 - 316. [Abstract] [Full Text] [PDF]
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F. Song, Z. Guan, I. E. Gienapp, T. Shawler, J. Benson, and C. C. Whitacre The Thymus Plays a Role in Oral Tolerance in Experimental Autoimmune Encephalomyelitis J. Immunol., August 1, 2006; 177(3): 1500 - 1509. [Abstract] [Full Text] [PDF]
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W. Hansen, K. Loser, A. M. Westendorf, D. Bruder, S. Pfoertner, C. Siewert, J. Huehn, S. Beissert, and J. Buer G Protein-Coupled Receptor 83 Overexpression in Naive CD4+CD25- T Cells Leads to the Induction of Foxp3+ Regulatory T Cells In Vivo J. Immunol., July 1, 2006; 177(1): 209 - 215. [Abstract] [Full Text] [PDF]
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A. Sharabi, H. Zinger, M. Zborowsky, Z. M. Sthoeger, and E. Mozes A peptide based on the complementarity-determining region 1 of an autoantibody ameliorates lupus by up-regulating CD4+CD25+ cells and TGF-beta PNAS, June 6, 2006; 103(23): 8810 - 8815. [Abstract] [Full Text] [PDF]
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N. R. Locke, S. Stankovic, D. P. Funda, and L. C. Harrison TCR{gamma}{delta} Intraepithelial Lymphocytes Are Required for Self-Tolerance. J. Immunol., June 1, 2006; 176(11): 6553 - 6559. [Abstract] [Full Text] [PDF]
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F. Fallarino, U. Grohmann, S. You, B. C. McGrath, D. R. Cavener, C. Vacca, C. Orabona, R. Bianchi, M. L. Belladonna, C. Volpi, et al. The Combined Effects of Tryptophan Starvation and Tryptophan Catabolites Down-Regulate T Cell Receptor {zeta}-Chain and Induce a Regulatory Phenotype in Naive T Cells. J. Immunol., June 1, 2006; 176(11): 6752 - 6761. [Abstract] [Full Text] [PDF]
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 B. Valzasina, S. Piconese, C. Guiducci, and M. P. Colombo Tumor-Induced Expansion of Regulatory T Cells by Conversion of CD4+CD25- Lymphocytes Is Thymus and Proliferation Independent. Cancer Res., April 15, 2006; 66(8): 4488 - 4495. [Abstract] [Full Text] [PDF]
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A. L. Every, D. R. Kramer, S. I. Mannering, A. M. Lew, and L. C. Harrison Intranasal Vaccination with Proinsulin DNA Induces Regulatory CD4+ T Cells That Prevent Experimental Autoimmune Diabetes. J. Immunol., April 15, 2006; 176(8): 4608 - 4615. [Abstract] [Full Text] [PDF]
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M. Ono, J. Shimizu, Y. Miyachi, and S. Sakaguchi Control of Autoimmune Myocarditis and Multiorgan Inflammation by Glucocorticoid-Induced TNF Receptor Family-Related Proteinhigh, Foxp3-Expressing CD25+ and CD25- Regulatory T Cells. J. Immunol., April 15, 2006; 176(8): 4748 - 4756. [Abstract] [Full Text] [PDF]
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C. Lyddane, B. U. Gajewska, E. Santos, P. D. King, G. C. Furtado, and M. Sadelain Cutting Edge: CD28 Controls Dominant Regulatory T Cell Activity during Active Immunization J. Immunol., March 15, 2006; 176(6): 3306 - 3310. [Abstract] [Full Text] [PDF]
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D. Alvarez, F. K. Swirski, T.-C. Yang, R. Fattouh, K. Croitoru, J. L. Bramson, M. R. Stampfli, and M. Jordana Inhalation Tolerance Is Induced Selectively in Thoracic Lymph Nodes but Executed Pervasively at Distant Mucosal and Nonmucosal Tissues J. Immunol., February 15, 2006; 176(4): 2568 - 2580. [Abstract] [Full Text] [PDF]
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M. Ghoreishi and J. P. Dutz Tolerance Induction by Transcutaneous Immunization through Ultraviolet-Irradiated Skin Is Transferable through CD4+CD25+ T Regulatory Cells and Is Dependent on Host-Derived IL-10 J. Immunol., February 15, 2006; 176(4): 2635 - 2644. [Abstract] [Full Text] [PDF]
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S. G. Zheng, L. Meng, J. H. Wang, M. Watanabe, M. L. Barr, D. V. Cramer, J. D. Gray, and D. A. Horwitz Transfer of regulatory T cells generated ex vivo modifies graft rejection through induction of tolerogenic CD4+CD25+ cells in the recipient Int. Immunol., February 1, 2006; 18(2): 279 - 289. [Abstract] [Full Text] [PDF]
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S. Chattopadhyay, S. Mehrotra, A. Chhabra, U. Hegde, B. Mukherji, and N. G. Chakraborty Effect of CD4+CD25+ and CD4+CD25- T Regulatory Cells on the Generation of Cytolytic T Cell Response to a Self but Human Tumor-Associated Epitope In Vitro J. Immunol., January 15, 2006; 176(2): 984 - 990. [Abstract] [Full Text] [PDF]
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M. Marski, S. Kandula, J. R. Turner, and C. Abraham CD18 Is Required for Optimal Development and Function of CD4+CD25+ T Regulatory Cells J. Immunol., December 15, 2005; 175(12): 7889 - 7897. [Abstract] [Full Text] [PDF]
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P. Romagnoli, D. Hudrisier, and J. P. M. van Meerwijk Molecular Signature of Recent Thymic Selection Events on Effector and Regulatory CD4+ T Lymphocytes J. Immunol., November 1, 2005; 175(9): 5751 - 5758. [Abstract] [Full Text] [PDF]
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W. Ise, K. Nakamura, N. Shimizu, H. Goto, K. Fujimoto, S. Kaminogawa, and S. Hachimura Orally Tolerized T Cells Can Form Conjugates with APCs but Are Defective in Immunological Synapse Formation J. Immunol., July 15, 2005; 175(2): 829 - 838. [Abstract] [Full Text] [PDF]
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Y. Chung, S.-H. Lee, D.-H. Kim, and C.-Y. Kang Complementary role of CD4+CD25+ regulatory T cells and TGF-{beta} in oral tolerance J. Leukoc. Biol., June 1, 2005; 77(6): 906 - 913. [Abstract] [Full Text] [PDF]
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J. D. Carter, G. M. Calabrese, M. Naganuma, and U. Lorenz Deficiency of the Src Homology Region 2 Domain-Containing Phosphatase 1 (SHP-1) Causes Enrichment of CD4+CD25+ Regulatory T Cells J. Immunol., June 1, 2005; 174(11): 6627 - 6638. [Abstract] [Full Text] [PDF]
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A. P. Treschow, J. Backlund, R. Holmdahl, and S. Issazadeh-Navikas Intrinsic Tolerance in Autologous Collagen-Induced Arthritis Is Generated by CD152-Dependent CD4+ Suppressor Cells J. Immunol., June 1, 2005; 174(11): 6742 - 6750. [Abstract] [Full Text] [PDF]
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K. M. Thorstenson, L. Herzovi, and A. Khoruts A model of suppression of the antigen-specific CD4 T cell response by regulatory CD25+CD4 T cells in vivo Int. Immunol., April 1, 2005; 17(4): 335 - 342. [Abstract] [Full Text] [PDF]
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D. W. Smith and C. Nagler-Anderson Preventing Intolerance: The Induction of Nonresponsiveness to Dietary and Microbial Antigens in the Intestinal Mucosa J. Immunol., April 1, 2005; 174(7): 3851 - 3857. [Abstract] [Full Text] [PDF]
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J. M. Herndon, P. M. Stuart, and T. A. Ferguson Peripheral Deletion of Antigen-Specific T Cells Leads to Long-Term Tolerance Mediated by CD8+ Cytotoxic Cells J. Immunol., April 1, 2005; 174(7): 4098 - 4104. [Abstract] [Full Text] [PDF]
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M. R. Walker, B. D. Carson, G. T. Nepom, S. F. Ziegler, and J. H. Buckner De novo generation of antigen-specific CD4+CD25+ regulatory T cells from human CD4+CD25- cells PNAS, March 15, 2005; 102(11): 4103 - 4108. [Abstract] [Full Text] [PDF]
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T. Higuchi, T. Maruyama, A. Jaramillo, and T. Mohanakumar Induction of Obliterative Airway Disease in Murine Tracheal Allografts by CD8+ CTLs Recognizing a Single Minor Histocompatibility Antigen J. Immunol., February 15, 2005; 174(4): 1871 - 1878. [Abstract] [Full Text] [PDF]
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S. Liang, P. Alard, Y. Zhao, S. Parnell, S. L. Clark, and M. M. Kosiewicz Conversion of CD4+ CD25- cells into CD4+ CD25+ regulatory T cells in vivo requires B7 costimulation, but not the thymus J. Exp. Med., January 3, 2005; 201(1): 127 - 137. [Abstract] [Full Text] [PDF]
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M. A. Curotto de Lafaille, A. C. Lino, N. Kutchukhidze, and J. J. Lafaille CD25- T Cells Generate CD25+Foxp3+ Regulatory T Cells by Peripheral Expansion J. Immunol., December 15, 2004; 173(12): 7259 - 7268. [Abstract] [Full Text] [PDF]
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T. A. Baldwin, K. A. Hogquist, and S. C. Jameson The Fourth Way? Harnessing Aggressive Tendencies in the Thymus J. Immunol., December 1, 2004; 173(11): 6515 - 6520. [Abstract] [Full Text] [PDF]
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 D. T. Nardelli, M. A. Burchill, D. M. England, J. Torrealba, S. M. Callister, and R. F. Schell Association of CD4+ CD25+ T Cells with Prevention of Severe Destructive Arthritis in Borrelia burgdorferi-Vaccinated and Challenged Gamma Interferon-Deficient Mice Treated with Anti-Interleukin-17 Antibody Clin. Vaccine Immunol., November 1, 2004; 11(6): 1075 - 1084. [Abstract] [Full Text] [PDF]
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M. Sela and E. Mozes Therapeutic vaccines in autoimmunity PNAS, October 5, 2004; 101(suppl_2): 14586 - 14592. [Abstract] [Full Text] [PDF]
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Z. Liu and L. Lefrancois Intestinal Epithelial Antigen Induces Mucosal CD8 T Cell Tolerance, Activation, and Inflammatory Response J. Immunol., October 1, 2004; 173(7): 4324 - 4330. [Abstract] [Full Text] [PDF]
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D. Yadav, V. Judkowski, M. Flodstrom-Tullberg, L. Sterling, W. L. Redmond, L. Sherman, and N. Sarvetnick B7-2 (CD86) Controls the Priming of Autoreactive CD4 T Cell Response against Pancreatic Islets J. Immunol., September 15, 2004; 173(6): 3631 - 3639. [Abstract] [Full Text] [PDF]
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H.-B. Park, D.-J. Paik, E. Jang, S. Hong, and J. Youn Acquisition of anergic and suppressive activities in transforming growth factor-{beta}-costimulated CD4+CD25- T cells Int. Immunol., August 1, 2004; 16(8): 1203 - 1213. [Abstract] [Full Text] [PDF]
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W. R. Godfrey, Y. G. Ge, D. J. Spoden, B. L. Levine, C. H. June, B. R. Blazar, and S. B. Porter In vitro-expanded human CD4+CD25+ T-regulatory cells can markedly inhibit allogeneic dendritic cell-stimulated MLR cultures Blood, July 15, 2004; 104(2): 453 - 461. [Abstract] [Full Text] [PDF]
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 N. Parameswaran, D. J. Samuvel, R. Kumar, S. Thatai, V. Bal, S. Rath, and A. George Oral Tolerance in T Cells Is Accompanied by Induction of Effector Function in Lymphoid Organs after Systemic Immunization Infect. Immun., July 1, 2004; 72(7): 3803 - 3811. [Abstract] [Full Text] [PDF]
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M. Apostolaki and N. A. Williams Nasal Delivery of Antigen with the B Subunit of Escherichia coli Heat-Labile Enterotoxin Augments Antigen-Specific T-Cell Clonal Expansion and Differentiation Infect. Immun., July 1, 2004; 72(7): 4072 - 4080. [Abstract] [Full Text] [PDF]
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M. R. Karlsson, J. Rugtveit, and P. Brandtzaeg Allergen-responsive CD4+CD25+ Regulatory T Cells in Children who Have Outgrown Cow's Milk Allergy J. Exp. Med., June 21, 2004; 199(12): 1679 - 1688. [Abstract] [Full Text] [PDF]
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I. Apostolou and H. von Boehmer In Vivo Instruction of Suppressor Commitment in Naive T Cells J. Exp. Med., May 17, 2004; 199(10): 1401 - 1408. [Abstract] [Full Text] [PDF]
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Y. Peng, Y. Laouar, M. O. Li, E. A. Green, and R. A. Flavell TGF-{beta} regulates in vivo expansion of Foxp3-expressing CD4+CD25+ regulatory T cells responsible for protection against diabetes PNAS, March 30, 2004; 101(13): 4572 - 4577. [Abstract] [Full Text] [PDF]
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J. Huehn, K. Siegmund, J. C.U. Lehmann, C. Siewert, U. Haubold, M. Feuerer, G. F. Debes, J. Lauber, O. Frey, G. K. Przybylski, et al. Developmental Stage, Phenotype, and Migration Distinguish Naive- and Effector/Memory-like CD4+ Regulatory T Cells J. Exp. Med., February 2, 2004; 199(3): 303 - 313. [Abstract] [Full Text] [PDF]
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P. Zhou, R. Borojevic, C. Streutker, D. Snider, H. Liang, and K. Croitoru Expression of Dual TCR on DO11.10 T Cells Allows for Ovalbumin-Induced Oral Tolerance to Prevent T Cell-Mediated Colitis Directed against Unrelated Enteric Bacterial Antigens J. Immunol., February 1, 2004; 172(3): 1515 - 1523. [Abstract] [Full Text] [PDF]
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A. Cavani, F. Nasorri, C. Ottaviani, S. Sebastiani, O. De Pita, and G. Girolomoni Human CD25+ Regulatory T Cells Maintain Immune Tolerance to Nickel in Healthy, Nonallergic Individuals J. Immunol., December 1, 2003; 171(11): 5760 - 5768. [Abstract] [Full Text] [PDF]
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B. Dubois, L. Chapat, A. Goubier, M. Papiernik, J.-F. Nicolas, and D. Kaiserlian Innate CD4+CD25+ regulatory T cells are required for oral tolerance and inhibition of CD8+ T cells mediating skin inflammation Blood, November 1, 2003; 102(9): 3295 - 3301. [Abstract] [Full Text] [PDF]
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L. S.K. Walker, A. Chodos, M. Eggena, H. Dooms, and A. K. Abbas Antigen-dependent Proliferation of CD4+ CD25+ Regulatory T Cells In Vivo J. Exp. Med., July 21, 2003; 198(2): 249 - 258. [Abstract] [Full Text] [PDF]
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T. Kaji, S. Hachimura, W. Ise, and S. Kaminogawa Proteome Analysis Reveals Caspase Activation in Hyporesponsive CD4 T Lymphocytes Induced in Vivo by the Oral Administration of Antigen J. Biol. Chem., July 18, 2003; 278(30): 27836 - 27843. [Abstract] [Full Text] [PDF]
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A. Boitelle, H. E. Scales, C. Di Lorenzo, E. Devaney, M. W. Kennedy, P. Garside, and C. E. Lawrence Investigating the Impact of Helminth Products on Immune Responsiveness Using a TCR Transgenic Adoptive Transfer System J. Immunol., July 1, 2003; 171(1): 447 - 454. [Abstract] [Full Text] [PDF]
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W. W. J. Unger, W. Jansen, D. A. W. Wolvers, A. G. S. van Halteren, G. Kraal, and J. N. Samsom Nasal tolerance induces antigen-specific CD4+CD25- regulatory T cells that can transfer their regulatory capacity to naive CD4+ T cells Int. Immunol., June 1, 2003; 15(6): 731 - 739. [Abstract] [Full Text] [PDF]
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M. Paas-Rozner, M. Sela, and E. Mozes A dual altered peptide ligand down-regulates myasthenogenic T cell responses by up-regulating CD25- and CTLA-4-expressing CD4+ T cells PNAS, May 27, 2003; 100(11): 6676 - 6681. [Abstract] [Full Text] [PDF]
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S. Grundstrom, L. Cederbom, A. Sundstedt, P. Scheipers, and F. Ivars Superantigen-Induced Regulatory T Cells Display Different Suppressive Functions in the Presence or Absence of Natural CD4+CD25+ Regulatory T Cells In Vivo J. Immunol., May 15, 2003; 170(10): 5008 - 5017. [Abstract] [Full Text] [PDF]
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C. Vasu, S. R. Gorla, B. S. Prabhakar, and M. J. Holterman Targeted engagement of CTLA-4 prevents autoimmune thyroiditis Int. Immunol., May 1, 2003; 15(5): 641 - 654. [Abstract] [Full Text] [PDF]
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N. M. Tsuji, K. Mizumachi, and J.-i. Kurisaki Antigen-specific, CD4+CD25+ regulatory T cell clones induced in Peyer's patches Int. Immunol., April 1, 2003; 15(4): 525 - 534. [Abstract] [Full Text] [PDF]
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C. T. Moses, K. M. Thorstenson, S. C. Jameson, and A. Khoruts Competition for self ligands restrains homeostatic proliferation of naive CD4 T cells PNAS, February 4, 2003; 100(3): 1185 - 1190. [Abstract] [Full Text] [PDF]
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A. Sundstedt, E. J. O'Neill, K. S. Nicolson, and D. C. Wraith Role for IL-10 in Suppression Mediated by Peptide-Induced Regulatory T Cells In Vivo J. Immunol., February 1, 2003; 170(3): 1240 - 1248. [Abstract] [Full Text] [PDF]
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K. Asai, S. Hachimura, M. Kimura, T. Toraya, M. Yamashita, T. Nakayama, and S. Kaminogawa T Cell Hyporesponsiveness Induced by Oral Administration of Ovalbumin Is Associated with Impaired NFAT Nuclear Translocation and p27kip1 Degradation J. Immunol., November 1, 2002; 169(9): 4723 - 4731. [Abstract] [Full Text] [PDF]
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J. Lehmann, J. Huehn, M. de la Rosa, F. Maszyna, U. Kretschmer, V. Krenn, M. Brunner, A. Scheffold, and A. Hamann Expression of the integrin alpha Ebeta 7 identifies unique subsets of CD25+ as well as CD25- regulatory T cells PNAS, October 1, 2002; 99(20): 13031 - 13036. [Abstract] [Full Text] [PDF]
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L. Zaliauskiene, S. Kang, K. Sparks, K. R. Zinn, L. M. Schwiebert, C. T. Weaver, and J. F. Collawn Enhancement of MHC Class II-Restricted Responses by Receptor-Mediated Uptake of Peptide Antigens J. Immunol., September 1, 2002; 169(5): 2337 - 2345. [Abstract] [Full Text] [PDF]
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H. Y. Wu, F. J. Ward, and N. A. Staines Histone Peptide-Induced Nasal Tolerance: Suppression of Murine Lupus J. Immunol., July 15, 2002; 169(2): 1126 - 1134. [Abstract] [Full Text] [PDF]
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 P. M. Cobelens, A. Kavelaars, R. van der Zee, W. van Eden, and C. J. Heijnen Dynamics of mycobacterial HSP65-induced T-cell cytokine expression during oral tolerance induction in adjuvant arthritis Rheumatology, July 1, 2002; 41(7): 775 - 779. [Abstract] [Full Text] [PDF]
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P. Martin, G. M. del Hoyo, F. Anjuere, C. F. Arias, H. H. Vargas, A. Fernandez-L, V. Parrillas, and C. Ardavin Characterization of a new subpopulation of mouse CD8alpha + B220+ dendritic cells endowed with type 1 interferon production capacity and tolerogenic potential Blood, June 28, 2002; 100(2): 383 - 390. [Abstract] [Full Text] [PDF]
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S. Hori, M. Haury, A. Coutinho, and J. Demengeot Specificity requirements for selection and effector functions of CD25+4+ regulatory T cells in anti-myelin basic protein T cell receptor transgenic mice PNAS, June 11, 2002; 99(12): 8213 - 8218. [Abstract] [Full Text] [PDF]
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E. Chiffoleau, G. Beriou, P. Dutartre, C. Usal, J.-P. Soulillou, and M. C. Cuturi Role for Thymic and Splenic Regulatory CD4+ T Cells Induced by Donor Dendritic Cells in Allograft Tolerance by LF15-0195 Treatment J. Immunol., May 15, 2002; 168(10): 5058 - 5069. [Abstract] [Full Text] [PDF]
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X. Zhang, L. Izikson, L. Liu, and H. L. Weiner Activation of CD25+CD4+ Regulatory T Cells by Oral Antigen Administration J. Immunol., October 15, 2001; 167(8): 4245 - 4253. [Abstract] [Full Text] [PDF]
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