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Laboratory of Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
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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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- and ß-chains (6, 9),
and CD4+ T cells isolated from the lymph node (LN) draining
the stomach of mice with gastritis proliferate in response to this
enzyme (5, 10). In addition, transgenic (Tg) mice expressing the H/K
ATPase ß-chain under control of the MHC class II promotor do not
develop gastritis after d3Tx, but still develop disease in other
organs (11). A similar spectrum of organ-specific autoimmunity can be induced by a variety of other manipulations of the lymphoid system (reviewed in 12 . Organ-specific autoimmunity develops in T cell-deficient recipients after transplantation of neonatal thymi as well as transfer of neonatal spleen cells or adult thymocytes (2, 13, 14, 15). Second, cyclosporin treatment of neonatal BALB/c mice induces autoimmune destruction in a variety of organs (16). Third, autoimmunity can also be induced in adult animals by repeated total body irradiation (17) or adult thymectomy, followed by cyclophosphamide treatment or irradiation (18, 19). Although several distinct mechanisms may be involved in the generation of autoimmunity in these models, one common feature of these as well as other experimental models of autoimmunity (20, 21) is that autoreactive T cells are selectively activated in animals with T cell lymphopenia.
Two fundamentally different models have been proposed to explain this association between lymphopenia and autoimmunity. In both models, normal adult mice contain autoreactive T cells. In the "empty space" model (22), the paucity of T cells in the peripheral lymphoid organs permits the expansion of the precursors of autoreactive T cells because the T lymphopenic environment facilitates the interaction of autoreactive T cells with professional APC. Such activated autoreactive T cells could then migrate to nonlymphoid organs and induce organ-specific autoimmunity. The second model (23) proposes that the lymphopenic state results in the selective absence of a critical population of regulatory T cells that continuously suppress the activation of autoreactive T cells. Strong support for the existence of such regulatory T cells has been obtained recently by the demonstration that Ab- and complement-mediated depletion of the minor (10%) subpopulation of CD4+ T cells in normal adult peripheral lymphoid tissues that coexpress CD4 and C25 generates a population of CD4+CD25- T cells that are potent inducers of autoimmunity when injected into nu/nu mice (24); furthermore, the induction of autoimmunity can be prevented by cotransfer of the CD4+CD25+ population (24). However, interpretation of the results of this study is complicated by the requirement to transfer the disease inducing population to a T cell-deficient environment for autoimmunity to become manifest. Thus, the empty space of the recipient mice may still provide an important component to disease pathogenesis.
In this work, we further characterize the capacity of CD4+CD25+ cells to inhibit organ-specific autoimmunity. We demonstrate that this minor subpopulation of T cells is not only able to suppress the induction of autoimmune effectors after d3Tx, but is also capable of suppressing disease induced by cloned autoantigen-specific T effector cells. Second, we show that the CD4+CD25+ cells are members of a unique lineage of professional immunoregulatory T cells. Finally, we provide strong evidence that the absence of CD4+CD25+ cells is primarily responsible for the susceptibility of lymphopenic animals to develop autoimmunity, as Tg mice that contain CD4+ T cells that express only a single TCR and very low numbers of CD4+CD25+ cells are highly susceptible to disease following transfer of autoantigen-specific T cell clones, while normal mice are relatively resistant. Taken together, these results provide an impetus for further studies to examine the critical role of suppressor T cells in controlling susceptibility to autoimmune disease in experimental animals and humans.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c and BALB/c-timed pregnant mice were purchased from National Cancer Institute (Frederick, MD). The day of birth was taken as day 0 of age. Three-day-old pups were thymectomized, as described (14). BALB/c nu/nu and C.B-17 SCID mice were purchased from Charles River Laboratories (Raleigh, NC) and Taconic (Germantown, NY), respectively, housed in sterile cages, and received autoclaved food and acidified water. BALB/c DO.11.10 TCR-Tg animals (25) were received from Dr. M. Jenkins (University of Minnesota Medical School, Minneapolis, MN). To obtain mice containing T cells expressing exclusively the Tg TCR and no endogenous TCR chains, the DO.11.10 mice were bred to C.B-17 SCID mice and housed in sterile cages. Only mice of the F2 generation that were devoid of B cells and exclusively expressed the DO.11.10 TCR clonotype (KJ1-26+) (25) were used for the experiments.
Flow cytometry
Cells (1 x 105 to 1 x
106) were first incubated with Fc block (PharMingen, San
Diego, CA) to prevent nonspecific binding, and then reacted with FITC
anti-TCR V2, PE anti-TCR Vß2, FITC or PE anti-CD4,
FITC anti-CD3 (2C11), PE anti-CD25 (3C7), or isotype-matched
control Ab (all from PharMingen). To determine the percentage of T
lymphocytes bearing the DO.11.10 TCR in Tg mice, blood lymphocytes were
incubated with KJ1-26 supernatant (1/10 dilution) (25) and then reacted
with FITC goat anti-mouse IgG F(ab')2 (Biosource,
Camarillo, CA) and PE anti-CD4. Viable cells (FSC/SSC or
7-amino-actinomycin D (Sigma Chemical Co., St. Louis, MO) exclusion of
dead cells) were then analyzed on a FACScan using CellQuest software
(Becton Dickinson, Mountain View, CA).
Preparation of cell populations for the treatment of d3Tx animals
Spleen and LN were harvested from 6- to 8-wk-old BALB/c mice or from 6- to 12-wk-old (DO.11.10 x SCID)F2 mice. Single cell suspensions were prepared by mashing the organs through a wire mesh into 5% FCS/HBSS. Spleen cells were depleted of erythrocytes by a 1-min treatment with ammonium-chloride-lysing buffer. LN and spleen cells were pooled in 5% FCS/HBSS, an aliquot of cells was incubated with PE anti-CD4 and FITC anti-CD3 mAb, and the percentage of CD4+ cells was determined in a FACScan. The remaining cells of both groups were washed and resuspended in PBS at 5 x 107 CD4+ cells/ml each. Two hundred microliters of lymphocyte suspension (1 x 107 CD4 T cells, 2–3 x 107 total cells) were injected i.p. into 10 day-old d3Tx animals. A control group of d3Tx mice received PBS only. To activate the TCR-Tg T cells, some of the recipients were immunized with OVA (100 µg) in 50 µl of CFA or with CFA alone i.p. 1 day after cell transfer. To prepare CD25- cells, BALB/c lymphocytes were incubated with rat anti-mouse CD25 mAb 7D4 (107 cells in 125 µl 2% FCS/HBSS + 1.3 µl 7D4 ascites) for 30 min on ice, followed by low-tox M rabbit complement (Cedarlane, Hornby, Ontario) for 40 min at 37°C. Aliquots of treated and control lymphocytes were reacted with PE-conjugated anti-CD25 mAb 3C7 and FITC anti-CD4 mAb and analyzed by FACS to verify complete depletion of CD25+ cells. CD25- or untreated spleen cells (2 x 107, each containing 25% CD4+ cells) were then injected i.p. into 10-day-old d3Tx mice in 200 µl PBS.
Detection of anti-parietal cell Ab (PCAb) and histologic evaluation of autoimmune gastritis
PCAb were detected by immunofluorescence on cryostat sections of
normal BALB/c stomach, as described (14). For histologic evaluation of
gastritis, stomachs were removed, fixed in Bouin’s solution,
sectioned, and stained with hematoxylin and eosin (American Histolabs,
Rockville, MD). Cellular infiltrates and tissue damage were read
"blind" by two investigators and scored as follows: Grade 0.5 to
1.5, normal gastric mucosa that contained a few lymphocytes scattered
throughout the submucosa. Grade 2, small aggregates containing three to
four layers of cells in the mucosa or sparse infiltrates of cells in
the submucosa covering 
5% of the section. Grade 3, frequent and
larger infiltrates extending into the mucosa. Grade 4, infiltrates
spanning half to the entire width of the mucosa. Grade 5, partial or
complete (grade 6) obliteration of parietal and chief cells with
hyperplasia of mucous and epithelial cells.
Preparation of gastric microsomes and recombinant H/K ATPase-expressing insect cell membranes
H/K ATPase-enriched rabbit gastric microsomes were prepared as
described previously (5). The protein concentration of the microsomes
was measured using the Bio-Rad protein assay (Bio-Rad, Hercules, CA)
and ranged from 1.5 to 4.5 mg/ml. Baculovirus expressing the H/K ATPase
- and ß-chains (DLZßAS) was obtained from Dr. De Pont
(University of Nijmegen, Nijmegen, The Netherlands) (26). For
production of viral stocks, 70% confluent insect cell monolayers
(SF21, a gift of Dr. S. Chen-Kiang, Cornell University School of
Medicine, New York, NY) or 2 x 106 cells/ml in
spinner flasks were infected with a multiplicity of infection of 0.5,
and infection was allowed to proceed for 4 to 5 days. The culture
medium was harvested, cells were pelleted, and the supernatant
containing approximately 1 x 107 plaque-forming units
was filtered twice through 0.2 µm and stored at 4°C. For H/K ATPase
production, 2 x 106/ml SF21 cells were infected in
spinner flasks at 5 to 10 multiplicity of infection. The cells were
harvested on day 3, resuspended at 1 x 107 cells/ml
in homogenization buffer (5 mM Tris-HCl, pH, 7.5, 0.25 M sucrose, 2 mM
EDTA, and 1 mM PMSF), and homogenized three times for 1 min on ice
using an OMNI tissue homogenizer (PGC Scientifics, Gaithersburg, MD).
Lysates were cleared of cell debris and bigger organelles by 10-min
centrifugation at 600 x g, followed by 4000 x
g. Cell membranes were then pelleted in 4-ml polycarbonate
tubes for 30 min at 100,000 x g (TLA 100.3 rotor;
Beckman Instruments, Palo Alto, CA) and resuspended in 1 ml storage
buffer (50 mM HEPES, 1 mM EDTA, 1 mM PMSF, and 1 µM leupeptin). The
protein concentration and the H/K ATPase content of the microsomes and
insect cell membranes were determined as previously described
(5).
Preparation of gastric LN cells, proliferation assay, and generation of H/K ATPase-reactive T cell lines/clones
Gastric LN from nu/nu mice injected with
CD25- spleen cells 3 mo earlier were pooled; single cell
suspensions were prepared and stimulated in vitro with various
concentrations of gastric microsomes; and Ag proliferation was measured
as described previously (5). H/K ATPase-reactive T cell lines were
generated from gastric LN cells of d3Tx animals, as described (5).
Established cell lines were cloned by limiting dilution. To test the
specificity of the cell lines/clones, 4 x 104 T cells
were incubated with 5 x 105 irradiated BALB/c spleen
cells (3000 rad) and graded concentrations of gastric microsomal Ag or
recombinant H/K ATPase. Cultures were pulsed with [3H]TdR
for the last 16 h of the 40-h incubation, and results are
expressed as mean cpm of triplicate wells. To induce gastritis, cells
were harvested 3 days after restimulation. T cell blasts were counted,
and 1 to 25 x 106 blasts were injected i.v. in 200
µl PBS into various recipient animals. In some experiments, normal
BALB/c spleen cells (50–100 x 106) or 1 to 2 x
106 CD4+CD25+ (85% pure) were
coinjected with the T cell blasts (5 x 106). The
CD4+CD25+ population was purified from normal
LN cells by enriching for CD4+ T cells using T cell
purification columns (R&D Systems, Minneapolis, MN), followed by
CD8+ T cell depletion using anti-CD8+
magnetic beads (Miltenyi, Auburn, CA).
CD4+CD25+ cells were then purified by
incubation with biotin anti-CD25 (PharMingen), followed by
streptavidin-FITC (PharMingen), both at 15 µg/108 cells.
The cells were then labeled with anti-FITC magnetic microbeads
(Miltenyi) and purified on a positive selection column, according to
the manufacturer’s suggested protocol.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have demonstrated previously (5) that the effector cells that
mediate autoimmune gastritis in d3Tx mice recognize the proton pump of
gastric parietal cells, H/K ATPase. The ability to transfer autoimmune
gastritis with CD4+CD25- T cells, but not
with unseparated CD4+ T cells, from adult BALB/c mice to
nu/nu recipients (24), as well as the capacity to induce
gastritis in adult BALB/c animals by manipulations of peripheral
lymphoid tissues (17, 18, 19) strongly suggest that normal adult BALB/c
mice also contain H/K ATPase-reactive cells. We therefore treated
spleen/LN cells from adult BALB/c animals with anti-CD25 mAb and C
and injected the remaining cells into nu/nu mice. Twelve
weeks after the injection of the CD25- lymphocytes, 61%
of the nu/nu recipients had developed gastritis (Fig. 1
A). When the gastric
LN cells of the animals with significant disease were stimulated with
the H/K ATPase-enriched preparation of rabbit microsomes (Fig. 1B), a vigorous Ag-proliferative response was
observed that resembled in magnitude that seen with gastric LN cells
from d3Tx animals (see 5 . Unseparated LN cells from normal mice
do not respond to H/K ATPase (Ref. 5 and data not shown). This result
shows that normal BALB/c mice contain H/K ATPase-reactive T cells and
that these cells can be activated and expanded in the recipient
nu/nu mice.
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It has been proposed (27) that the
CD4+CD25+ cells may be deficient in
neonatal mice after thymectomy and that their absence is responsible
for the organ-specific autoimmunity observed. To directly test whether
CD25+ cells from adult mice are capable of inhibiting the
induction of gastritis after d3Tx, we compared the capacity of
unseparated normal spleen/LN cells from adult mice or spleen/LN cells
depleted of CD25+ cells to inhibit the development of
gastritis post-d3Tx. When d3Tx animals were injected on day 10 with
spleen/LN cells, the development of gastritis was totally abrogated
(Fig. 2A). In contrast,
injection of an equal number of spleen/LN cells that had been depleted
of CD25+ cells neither diminished nor enhanced the
incidence or severity of post-d3Tx-induced gastritis (Fig. 2A). These data strongly suggest that
CD25+ cells are critical in inhibiting the initiation of
gastritis post-d3Tx. Similar results have been reported by Asano et
al. (27).
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The inability of CD25- spleen/LN cells to
prevent the development of gastritis strongly suggests that the defect
in the d3Tx mice is not secondary to the empty space generated by the
removal of the thymus (22), as the lymphoid system in the reconstituted
animals should have been repopulated equally by both populations of
cells used in these studies. However, it is not clear from these
studies whether the CD25+ population is derived from normal
CD4+CD25- cells that have been activated in
vivo in response to normal antigenic stimulation or whether the
CD4+CD25+ are a unique population of
professional immunoregulatory cells. To address this question, we bred
BALB/c DO.11.10 TCR/Tg mice to C.B-17 SCID mice for two generations and
selected mice of the F2 generation in which all
CD4+ T cells expressed the DO.11.10 clonotypic TCR directed
against chicken OVA peptide 323–339 and which contained no
B220+ cells. It should initially be noted that the
percentage of CD4+ cells that express CD25 is much lower in
these TCR-Tg/SCID mice (2.7 +/- 0.8%, range 1.5–4.1%,
n = 11) compared with the percentage in several strains
of normal mice that we and others have studied (10%) (23 and data
not shown). As none of the Tg T cells from these mice can recognize the
H/K ATPase and thereby induce gastritis by themselves, we attempted to
inhibit the development of autoimmunity in d3Tx mice by injection of
the TCR-Tg T cells. Reconstitution of the d3Tx mice on day 10 with
CD4+ Tg T cells did not inhibit gastritis, while
reconstitution with the same number of T cells from conventional BALB/c
mice completely prevented the development of disease (Fig. 2
B). However, as the frequency of the
CD25+ cells differed markedly between the two populations,
it is possible that the absolute number of CD25+ cells
present in the Tg population may not have been high enough to prevent
gastritis. To rule out this possibility, we reconstituted d3Tx mice
with the TCR-Tg cells and immunized the mice with OVA/CFA. Although
this protocol resulted in expression of CD25 on up to 50% of the Tg T
cells (data not shown), no inhibition of gastritis was seen in the
reconstituted, immunized d3Tx mice (Fig. 2B). As the
injection of CFA alone blocks the development of diabetes in nonobese
diabetic mice (28), control unreconstituted d3Tx mice were injected
with OVA/CFA. In fact, such animals had a higher incidence of gastritis
than untreated d3Tx mice, but this difference was not statistically
significant (p = 0.1). Taken together, these
studies demonstrate that the mere induction of expression of CD25 on a
high percentage of T cells in vivo is insufficient to inhibit the
induction of autoimmune gastritis.
CD25+ cells inhibit gastritis induced by H/K ATPase-reactive effector T cells
Autoimmune diseases may potentially be blocked either by
preventing the primary activation of autoreactive T cells or by
preventing autoreactive effector T cells from inducing tissue
destruction. As the CD25+ cells prevented infiltration
of the gastric mucosa, tissue destruction, and PCAb production, it is
quite likely that the CD25+ cells prevented the initial
activation of autoreactive T cells after d3Tx. To evaluate whether the
CD25+ cells can also prevent gastritis by interfering with
the function of effector T cells, we generated H/K ATPase-reactive T
cell lines from d3Tx animals. Two of these cell lines, TXA-23 and
TXA-15.7, uniformly expressed CD4 and the V2/Vß2 TCR (Fig. 3A and data not shown) and
proliferated when stimulated with H/K ATPase-enriched rabbit microsomes
and rat H/K ATPase expressed on insect cell membranes (Fig. 3B and data not shown). The cell lines were then cloned by
limiting dilution and tested for their ability to induce gastritis in T
cell-deficient nu/nu and SCID recipients. The recipients
were killed 8 wk after cell transfer, and gastritis was evaluated
histologically. Marked destruction of gastric parietal cells was
observed in all recipients that received as few as 5 to 10 x
106 cloned V2/Vß2 T cells (Figs. 4 and 5).
It should be mentioned that in contrast to nu/nu recipients
of T cells from d3Tx mice, the nu/nu recipients of the
cloned lines did not develop PCAb (data not shown), presumably because
the lines produce a Th1 pattern of cytokines (IFN-
and TNF-, data
not shown) that is not adequate to provide B cell help. Thus, PCAb are
not necessary for tissue destruction.
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A). To distinguish
between the possibility that the failure of TXA-23 to induce disease in
normals was secondary to the presence of immunoregulatory
CD4+CD25+ cells or whether the transferred
cells were inhibited from homing to spleen/LN or to the gastric mucosa
secondary to competition by normal host T cells, we transferred TXA-23
cells into TCR-Tg/SCID mice. Interestingly, all of the TCR-Tg mice
developed severe gastritis (Fig. 6B). Although these
results are most consistent with the possibility that the failure of
TXA-23 cells to transfer disease to normal mice is secondary to the
presence of CD4+CD25+ cells, the total number
of CD4+ T cells recovered from TCR-Tg/SCID mice is
frequently only 30% of CD4+ T cells recovered from normal
mice. Thus, it remained possible that the susceptibility of the
TCR-Tg/SCID mice to disease was secondary to a quantitative deficiency
of normal CD4+ T cells. To directly test the inhibitory
capacity of the CD4+CD25+ T cells, TXA-23 cells
(5 x 106) were mixed with spleen cells (50–100
x 106) from BALB/c mice and injected into nu/nu
mice. Marked inhibition of the development of disease was seen when the
normal spleen cells were cotransferred (Fig. 7A). As it is
impossible to test whether CD4+CD25- cells
from normal spleen can inhibit disease, as they by themselves are
capable of inducing gastritis (Fig. 1 and 24 ,
CD4+CD25+ cells were purified from normal
spleen and cotransferred with TXA-23 cells into nu/nu
recipients. Unfortunately, we could only purify sufficient numbers of
cells to treat relatively few animals, but most of the nu/nu
mice receiving the mixture of TXA-23 cells and CD25+ cells
did not develop gastritis (Fig. 8),
thereby directly demonstrating that the function of autoreactive
effector T cells can be blocked by CD4+CD25+
regulatory cells in the absence of CD4+CD25- T
cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The induction of organ-specific autoimmune disease post-d3Tx has proven to be a useful model system for the analysis of the role of immunoregulatory T cells in the development of autoimmunity. In susceptible strains of mice, a high incidence of disease develops that can uniformly be prevented by reconstitution of the d3Tx animals with normal adult T lymphocytes by day 10 to 14 of life. The effectors (15, 23, 24) and suppressors (16, 33, 34, 35) of autoimmune disease in this model have both been shown convincingly to be CD4+ T cells, while CD8+ T cells or B cells appear to play minimal roles in mediating the pathology of or protection from autoimmune disease.
One major problem in the analysis of the immunoregulatory T cell
population in the d3Tx and other models of autoimmunity is the lack of
specific markers. Although the immunoregulatory cells have been defined
as expressing high levels of CD5 (33, 34) or low levels of CD45RB (20, 21), those populations comprise 80% and 30 to 40% of
CD4+ T cells, respectively. A recent major advance has been
made by Sakaguchi et al. (24, 27), who demonstrated that when the minor
(10%) subpopulation of CD4+ cells that coexpressed CD25
was depleted from suspensions of adult peripheral lymphoid tissues, the
remaining CD4+CD25- cells induced a syndrome
of organ-specific autoimmunity upon transfer to nu/nu
recipients that resembled that seen post-d3Tx. However, it has not yet
been determined whether the CD4+CD25+
population is a unique lineage of professional suppressor cells or
whether any activated T cells that expressed CD25 could exhibit
immmunoregulatory functions. Furthermore, a possible contribution of
the T lymphopenic environment could also not be addressed, as these
studies were all performed by transferring the potential autoimmune
effector cells to immunodeficient mice.
The results of the studies presented in this work have resolved several
of these important questions and clearly define the
CD4+CD25+ T cells as members of a potentially
unique lineage of regulatory T cells. First, the
CD4+CD25+ cells are the critical population
that prevents the development of autoimmunity post-d3Tx, as
reconstitution of d3Tx animals with spleen cell populations depleted of
CD25+ cells failed to prevent disease. It thus appears that
the regulatory cell population that controls the capacity of normal
CD4+CD25- T cells to induce autoimmunity upon
transfer to nu/nu mice is identical to the one that controls
the development of autoimmunity post-d3Tx. Although this result appears
to rule out the possibility that the prevention of autoimmunity in this
model is simply a result of filling up the empty space of the d3Tx
recipient, it remained possible that CD4+CD25-
cell population may add more putative autoreactive precursor cells to
the d3Tx animal, thus pushing the balance of filler vs autoreactive
cells to the latter. We directly addressed this question by
reconstituting the d3Tx animals with T cells from a TCR-Tg/SCID animal
that could recognize neither the autoantigen nor the autoreactive T
cells themselves in an anti-idiotypic fashion (36); however, the
cells from the TCR-Tg/SCID animal, although inert, could still compete
for APC, cytokines, and space. Although the T cells from the
TCR-Tg/SCID were completely incapable of suppressing disease,
interpretation of this experiment was also complicated because the
TCR-Tg/SCID CD4+ T cell population contained only 30%
of the CD25+ cells present in the CD4+
population from normal mice. This result by itself suggested that the
CD4+CD25+ population in normal mice was a
unique lineage that was reduced greatly in the TCR-Tg/SCID.
Furthermore, activation of the TCR-Tg/SCID cells with Ag in adjuvant,
while effective in inducing expression of CD25 on greater than 50% of
the CD4+ cells, did not result in prevention of disease.
These results are most consistent with the concept that the active
immunoregulatory population contained within the
CD4+CD25+ population in normal mice represents
a lineage of cells with unique immunoregulatory properties. The small
number of CD4+CD25+ cells in the TCR-Tg/SCID
population may express CD25 as a result of activation with
cross-reacting environmental Ags.
Irrespective of the mechanism whereby the immunoregulatory cells suppress disease, it has been widely assumed that they would function by inhibiting the generation of autoreactive effectors from their precursors. In most studies (34), including our own (unpublished observations), the d3Tx animals have to be reconstituted by day 10 to 14 of life to prevent disease. We were therefore surprised to observe that large numbers of cloned CD4+ H/K ATPase-specific T cells failed to transfer disease to normal mice, while nu/nu and SCID mice were susceptible to disease induction by approximately 25-fold fewer cells. As it seemed likely that the immunoregulatory CD4+CD25+ cells were responsible for prevention of disease in the normal mouse, we attempted to induce disease in the TCR-Tg/SCID mice by transfer of the H/K ATPase-reactive clone. In fact, the TCR-Tg/SCID mice developed more severe gastritis than the nu/nu or SCID mice, which suggests that nonspecific activation of the TCR-Tg/SCID T cells by the transferred cloned T cells actually enhanced the inflammatory process (37), which in turn may have led to additional cytokine production by the host cells. These results support the view that TCR-Tg/SCID mice do not possess the regulatory CD4+CD25+ cells needed to control autoimmunity. Furthermore, it appears likely that the CD4+CD25+ population is also responsible for the resistance of normal mice to the transfer of disease by the pathogenic clone, as the addition of normal spleen cells or highly purified CD4+CD25+ to the autoreactive effector T cells markedly suppressed their capacity to transfer disease into nu/nu recipients. The absence of CD4+CD25+ T cells may explain the high incidence of spontaneous encephalitis in mice transgenic for an anti-myelin basic protein TCR on a RAG-/- background (38), while mice with the same TCR on a conventional background exhibit a low incidence of spontaneous disease.
A number of important questions remain to be addressed about the CD4+CD25+ population, including the nature of the physiologic ligand recognized by their TCR (if any), whether they must be activated via the TCR to exert their suppressive functions, and how they mediate their suppressive effects. A number of studies have suggested that they may recognize the same Ag as the autoimmune effector cells, i.e., in the BALB/c d3Tx model, the H/K ATPase. However, these studies were based on the observation that female cells were less efficient at suppressing autoimmune disease in male mice than cells from adult males (4), and more recent studies (33) have not been able to reproduce these findings. In addition, intrathymic injection of the autoantigen (gastric parietal cells) did not lead to the deletion/inactivation of suppressor cells in the spleen (35), while it did prevent the development of autoimmune effectors. A second possible target for the TCR of the CD4+CD25+ is the TCR of the autoimmune effector cells. Suppression by CD4+ anti-Id-specific T cells has been described in experimental allergic encephalomyelitis (36), and a similar mechanism may be operative in gastritis (39). A variation of this model is that the immunoregulatory cells are anti-ergotypic (40) and become activated by the recognition of activation markers on the effector T cells. Finally, it is possible that this population is autoreactive and is activated by ubiquitously expressed Ags; they could then mediate bystander suppression by the secretion of suppressor cytokines (IL-4, IL-10, or TGF-ß) or could even exert suppression by a contact-dependent mechanism at the level of the autoimmune effector cells (Fas/Fas ligand) or at the level of the APC perhaps by competing for costimulatory molecules.
With the exception of the model that proposes that the suppressor cells are specific only for autoantigens, one problematic attribute of the suppressor population is how they discriminate between immune responses against autoantigens and foreign Ags. Perhaps they only suppress responses to autoantigens because they are generally of lower affinity at the level of TCR recognition. We strongly believe that the potent activity of the CD4+CD25+ cells is not only confined to autoimmunity observed after d3Tx and that studies to enhance their suppressive effects may prove to be fruitful in other models of organ-specific autoimmunity or in transplantation immunology (24); conversely, studies to inhibit their effects may be useful in augmenting the immune responses to tumor-related Ags that now represent well-studied autoantigens.
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Footnotes |
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2 Abbreviations used in this paper: d3Tx, thymectomized on day 3 of life; LN, lymph node; PCAb, anti-parietal cell antibody; PE, phycoerythrin; Tg, transgenic.
Received for publication July 18, 1997. Accepted for publication October 22, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and ß subunits of the gastric proton pump. Gastroenterology 101:287.[Medline]
-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155:1151.[Abstract]
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S.-J. Shieh, F.-C. Chou, P.-N. Yu, W.-C. Lin, D.-M. Chang, S. R. Roffler, and H.-K. Sytwu Transgenic Expression of Single-Chain Anti-CTLA-4 Fv on {beta} Cells Protects Nonobese Diabetic Mice from Autoimmune Diabetes J. Immunol., August 15, 2009; 183(4): 2277 - 2285. [Abstract] [Full Text] [PDF]
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 M. M. Collazo, D. Wood, K. H. T. Paraiso, E. Lund, R. W. Engelman, C.-T. Le, D. Stauch, K. Kotsch, and W. G. Kerr SHIP limits immunoregulatory capacity in the T-cell compartment Blood, March 26, 2009; 113(13): 2934 - 2944. [Abstract] [Full Text] [PDF]
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 J. Ji and M. W. Cloyd HIV-1 binding to CD4 on CD4+CD25+ regulatory T cells enhances their suppressive function and induces them to home to, and accumulate in, peripheral and mucosal lymphoid tissues: an additional mechanism of immunosuppression Int. Immunol., March 1, 2009; 21(3): 283 - 294. [Abstract] [Full Text] [PDF]
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M. Bonelli, A. Savitskaya, C.-W. Steiner, E. Rath, J. S. Smolen, and C. Scheinecker Phenotypic and Functional Analysis of CD4+CD25-Foxp3+ T Cells in Patients with Systemic Lupus Erythematosus J. Immunol., February 1, 2009; 182(3): 1689 - 1695. [Abstract] [Full Text] [PDF]
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 D. de Jong, A. Koster, A. Hagenbeek, J. Raemaekers, D. Veldhuizen, S. Heisterkamp, J. P. de Boer, and M. van Glabbeke Impact of the tumor microenvironment on prognosis in follicular lymphoma is dependent on specific treatment protocols Haematologica, January 1, 2009; 94(1): 70 - 77. [Abstract] [Full Text] [PDF]
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 S. K. Lathrop, N. A. Santacruz, D. Pham, J. Luo, and C.-S. Hsieh Antigen-specific peripheral shaping of the natural regulatory T cell population J. Exp. Med., December 22, 2008; 205(13): 3105 - 3117. [Abstract] [Full Text] [PDF]
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 K. F. Siemasko, J. Gao, V. L. Calder, R. Hanna, M. Calonge, S. C. Pflugfelder, J. Y. Niederkorn, and M. E. Stern In Vitro Expanded CD4+CD25+Foxp3+ Regulatory T Cells Maintain a Normal Phenotype and Suppress Immune-Mediated Ocular Surface Inflammation Invest. Ophthalmol. Vis. Sci., December 1, 2008; 49(12): 5434 - 5440. [Abstract] [Full Text] [PDF]
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 R. Simone, A. Zicca, and D. Saverino The frequency of regulatory CD3+CD8+CD28-CD25+ T lymphocytes in human peripheral blood increases with age J. Leukoc. Biol., December 1, 2008; 84(6): 1454 - 1461. [Abstract] [Full Text] [PDF]
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M. S. Wilson, J. T. Pesce, T. R. Ramalingam, R. W. Thompson, A. Cheever, and T. A. Wynn Suppression of Murine Allergic Airway Disease by IL-2:Anti-IL-2 Monoclonal Antibody-Induced Regulatory T Cells J. Immunol., November 15, 2008; 181(10): 6942 - 6954. [Abstract] [Full Text] [PDF]
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D. R. Tonkin, J. He, G. Barbour, and K. Haskins Regulatory T Cells Prevent Transfer of Type 1 Diabetes in NOD Mice Only When Their Antigen Is Present In Vivo J. Immunol., October 1, 2008; 181(7): 4516 - 4522. [Abstract] [Full Text] [PDF]
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H. Zhang, J. R. Podojil, X. Luo, and S. D. Miller Intrinsic and Induced Regulation of the Age-Associated Onset of Spontaneous Experimental Autoimmune Encephalomyelitis J. Immunol., October 1, 2008; 181(7): 4638 - 4647. [Abstract] [Full Text] [PDF]
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 S. Sharma, A. L. Dominguez, S. Z. Manrique, F. Cavallo, S. Sakaguchi, and J. Lustgarten Systemic Targeting of CpG-ODN to the Tumor Microenvironment with Anti-neu-CpG Hybrid Molecule and T Regulatory Cell Depletion Induces Memory Responses in BALB-neuT Tolerant Mice Cancer Res., September 15, 2008; 68(18): 7530 - 7540. [Abstract] [Full Text] [PDF]
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M. Nagar, H. Vernitsky, Y. Cohen, D. Dominissini, Y. Berkun, G. Rechavi, N. Amariglio, and I. Goldstein Epigenetic inheritance of DNA methylation limits activation-induced expression of FOXP3 in conventional human CD25-CD4+ T cells Int. Immunol., August 1, 2008; 20(8): 1041 - 1055. [Abstract] [Full Text] [PDF]
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A. L. Dominguez and J. Lustgarten Implications of Aging and Self-Tolerance on the Generation of Immune and Antitumor Immune Responses Cancer Res., July 1, 2008; 68(13): 5423 - 5431. [Abstract] [Full Text] [PDF]
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M. Poitrasson-Riviere, B. Bienvenu, A. Le Campion, C. Becourt, B. Martin, and B. Lucas Regulatory CD4+ T Cells Are Crucial for Preventing CD8+ T Cell-Mediated Autoimmunity J. Immunol., June 1, 2008; 180(11): 7294 - 7304. [Abstract] [Full Text] [PDF]
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 M Bonelli, K von Dalwigk, A Savitskaya, J S Smolen, and C Scheinecker Foxp3 expression in CD4+ T cells of patients with systemic lupus erythematosus: a comparative phenotypic analysis Ann Rheum Dis, May 1, 2008; 67(5): 664 - 671. [Abstract] [Full Text] [PDF]
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H. Tuovinen, E. Kekalainen, L. H. Rossi, J. Puntila, and T. Petteri Arstila Cutting Edge: Human CD4-CD8- Thymocytes Express FOXP3 in the Absence of a TCR J. Immunol., March 15, 2008; 180(6): 3651 - 3654. [Abstract] [Full Text] [PDF]
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B. Santner-Nanan, N. Seddiki, E. Zhu, V. Quent, A. Kelleher, B. F. de St Groth, and R. Nanan Accelerated age-dependent transition of human regulatory T cells to effector memory phenotype Int. Immunol., March 1, 2008; 20(3): 375 - 383. [Abstract] [Full Text] [PDF]
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 V. Dal Secco, A. Riccioli, F. Padula, E. Ziparo, and A. Filippini Mouse Sertoli Cells Display Phenotypical and Functional Traits of Antigen-Presenting Cells in Response to Interferon Gamma Biol Reprod, February 1, 2008; 78(2): 234 - 242. [Abstract] [Full Text] [PDF]
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F. J. Ward, A. M. Hall, L. S. Cairns, A. S. Leggat, S. J. Urbaniak, M. A. Vickers, and R. N. Barker Clonal regulatory T cells specific for a red blood cell autoantigen in human autoimmune hemolytic anemia Blood, January 15, 2008; 111(2): 680 - 687. [Abstract] [Full Text] [PDF]
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 M.-F. Liu, L.-H. Lin, C.-T. Weng, and M.-Y. Weng Decreased CD4+CD25+bright T cells in peripheral blood of patients with primary Sjogren's syndrome Lupus, January 1, 2008; 17(1): 34 - 39. [Abstract] [PDF]
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N. Wan, H. Dai, T. Wang, Y. Moore, X. X. Zheng, and Z. Dai Bystander Central Memory but Not Effector Memory CD8+ T Cells Suppress Allograft Rejection J. Immunol., January 1, 2008; 180(1): 113 - 121. [Abstract] [Full Text] [PDF]
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 L. Vence, A. K. Palucka, J. W. Fay, T. Ito, Y.-J. Liu, J. Banchereau, and H. Ueno Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma PNAS, December 26, 2007; 104(52): 20884 - 20889. [Abstract] [Full Text] [PDF]
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A. A. Hombach, D. Kofler, A. Hombach, G. Rappl, and H. Abken Effective Proliferation of Human Regulatory T Cells Requires a Strong Costimulatory CD28 Signal That Cannot Be Substituted by IL-2 J. Immunol., December 1, 2007; 179(11): 7924 - 7931. [Abstract] [Full Text] [PDF]
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A. D. Reynolds, R. Banerjee, J. Liu, H. E. Gendelman, and R. L. Mosley Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson's disease J. Leukoc. Biol., November 1, 2007; 82(5): 1083 - 1094. [Abstract] [Full Text] [PDF]
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R. Sutmuller, A. Garritsen, and G. J Adema Regulatory T cells and toll-like receptors: regulating the regulators Ann Rheum Dis, November 1, 2007; 66(suppl_3): iii91 - iii95. [Abstract] [Full Text] [PDF]
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G. Galazka, A. Jurewicz, W. Orlowski, M. Stasiolek, C. F. Brosnan, C. S. Raine, and K. Selmaj EAE Tolerance Induction with Hsp70-Peptide Complexes Depends on H60 and NKG2D Activity J. Immunol., October 1, 2007; 179(7): 4503 - 4512. [Abstract] [Full Text] [PDF]
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J. Kubach, P. Lutter, T. Bopp, S. Stoll, C. Becker, E. Huter, C. Richter, P. Weingarten, T. Warger, J. Knop, et al. Human CD4+CD25+ regulatory T cells: proteome analysis identifies galectin-10 as a novel marker essential for their anergy and suppressive function Blood, September 1, 2007; 110(5): 1550 - 1558. [Abstract] [Full Text] [PDF]
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Y. Peng, H. Shao, Y. Ke, P. Zhang, G. Han, H. J. Kaplan, and D. Sun Minimally Activated CD8 Autoreactive T Cells Specific for IRBP Express a High Level of Foxp3 and Are Functionally Suppressive Invest. Ophthalmol. Vis. Sci., May 1, 2007; 48(5): 2178 - 2184. [Abstract] [Full Text] [PDF]
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 J. G. Berdeja, A. Hess, D. M. Lucas, P. O'Donnell, R. F. Ambinder, L. F. Diehl, D. Carter-Brookins, S. Newton, and I. W. Flinn Systemic Interleukin-2 and Adoptive Transfer of Lymphokine-Activated Killer Cells Improves Antibody-Dependent Cellular Cytotoxicity in Patients with Relapsed B-Cell Lymphoma Treated with Rituximab Clin. Cancer Res., April 15, 2007; 13(8): 2392 - 2399. [Abstract] [Full Text] [PDF]
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M. S. Turner, P. A. Cohen, and O. J. Finn Lack of Effective MUC1 Tumor Antigen-Specific Immunity in MUC1-Transgenic Mice Results from a Th/T Regulatory Cell Imbalance That Can Be Corrected by Adoptive Transfer of Wild-Type Th Cells J. Immunol., March 1, 2007; 178(5): 2787 - 2793. [Abstract] [Full Text] [PDF]
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 A. M. Glas, L. Knoops, L. Delahaye, M. J. Kersten, R. E. Kibbelaar, L. A. Wessels, R. van Laar, J. H. J.M. van Krieken, J. W. Baars, J. Raemaekers, et al. Gene-Expression and Immunohistochemical Study of Specific T-Cell Subsets and Accessory Cell Types in the Transformation and Prognosis of Follicular Lymphoma J. Clin. Oncol., February 1, 2007; 25(4): 390 - 398. [Abstract] [Full Text] [PDF]
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A. Joetham, K. Takada, C. Taube, N. Miyahara, S. Matsubara, T. Koya, Y.-H. Rha, A. Dakhama, and E. W. Gelfand Naturally Occurring Lung CD4+CD25+ T Cell Regulation of Airway Allergic Responses Depends on IL-10 Induction of TGF-beta J. Immunol., February 1, 2007; 178(3): 1433 - 1442. [Abstract] [Full Text] [PDF]
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S. Sharma, A. L. Dominguez, and J. Lustgarten High Accumulation of T Regulatory Cells Prevents the Activation of Immune Responses in Aged Animals J. Immunol., December 15, 2006; 177(12): 8348 - 8355. [Abstract] [Full Text] [PDF]
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N. Bosco, F. Agenes, A. G. Rolink, and R. Ceredig Peripheral T Cell Lymphopenia and Concomitant Enrichment in Naturally Arising Regulatory T Cells: The Case of the Pre-T{alpha} Gene-Deleted Mouse J. Immunol., October 15, 2006; 177(8): 5014 - 5023. [Abstract] [Full Text] [PDF]
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P. J. Lucas, S.-J. Kim, C. L. Mackall, W. G. Telford, Y.-W. Chu, F. T. Hakim, and R. E. Gress Dysregulation of IL-15-mediated T-cell homeostasis in TGF-beta dominant-negative receptor transgenic mice Blood, October 15, 2006; 108(8): 2789 - 2795. [Abstract] [Full Text] [PDF]
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R. P. de Latour, H. C. Dujardin, F. Mishellany, O. Burlen-Defranoux, J. Zuber, R. Marques, J. Di Santo, A. Cumano, P. Vieira, and A. Bandeira Ontogeny, function, and peripheral homeostasis of regulatory T cells in the absence of interleukin-7 Blood, October 1, 2006; 108(7): 2300 - 2306. [Abstract] [Full Text] [PDF]
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K. Rezvani, S. Mielke, M. Ahmadzadeh, Y. Kilical, B. N. Savani, J. Zeilah, K. Keyvanfar, A. Montero, N. Hensel, R. Kurlander, et al. High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT Blood, August 15, 2006; 108(4): 1291 - 1297. [Abstract] [Full Text] [PDF]
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 D. T. Nardelli, T. F. Warner, S. M. Callister, and R. F. Schell Anti-CD25 Antibody Treatment of Mice Vaccinated and Challenged with Borrelia spp. Does Not Exacerbate Arthritis but Inhibits Borreliacidal Antibody Production. Clin. Vaccine Immunol., August 1, 2006; 13(8): 884 - 891. [Abstract] [Full Text] [PDF]
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 P. Alard, J. N. Manirarora, S. A. Parnell, J. L. Hudkins, S. L. Clark, and M. M. Kosiewicz Deficiency in NOD Antigen-Presenting Cell Function May Be Responsible for Suboptimal CD4+CD25+ T-Cell-Mediated Regulation and Type 1 Diabetes Development in NOD Mice. Diabetes, July 1, 2006; 55(7): 2098 - 2105. [Abstract] [Full Text] [PDF]
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H.-Y. Qin, R. Mukherjee, E. Lee-Chan, C. Ewen, R. C. Bleackley, and B. Singh A novel mechanism of regulatory T cell-mediated down-regulation of autoimmunity Int. Immunol., July 1, 2006; 18(7): 1001 - 1015. [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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A. Noble, A. Giorgini, and J. A. Leggat Cytokine-induced IL-10-secreting CD8 T cells represent a phenotypically distinct suppressor T-cell lineage Blood, June 1, 2006; 107(11): 4475 - 4483. [Abstract] [Full Text] [PDF]
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A. Sumoza-Toledo, A. D. Eaton, and A. Sarukhan Regulatory T Cells Inhibit Protein Kinase C{theta} Recruitment to the Immune Synapse of Naive T Cells with the Same Antigen Specificity J. Immunol., May 15, 2006; 176(10): 5779 - 5787. [Abstract] [Full Text] [PDF]
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M. Baumgart, F. Tompkins, J. Leng, and M. Hesse Naturally Occurring CD4+Foxp3+ Regulatory T Cells Are an Essential, IL-10-Independent Part of the Immunoregulatory Network in Schistosoma mansoni Egg-Induced Inflammation J. Immunol., May 1, 2006; 176(9): 5374 - 5387. [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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H. Keino, M. Takeuchi, T. Kezuka, T. Hattori, M. Usui, O. Taguchi, J. W. Streilein, and J. Stein-Streilein Induction of Eye-Derived Tolerance Does Not Depend on Naturally Occurring CD4+CD25+ T Regulatory Cells. Invest. Ophthalmol. Vis. Sci., March 1, 2006; 47(3): 1047 - 1055. [Abstract] [Full Text] [PDF]
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K. Rieger, C. Loddenkemper, J. Maul, T. Fietz, D. Wolff, H. Terpe, B. Steiner, E. Berg, S. Miehlke, M. Bornhauser, et al. Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD Blood, February 15, 2006; 107(4): 1717 - 1723. [Abstract] [Full Text] [PDF]
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N. N. Choileain, M. MacConmara, Y. Zang, T. J. Murphy, J. A. Mannick, and J. A. Lederer Enhanced Regulatory T Cell Activity Is an Element of the Host Response to Injury J. Immunol., January 1, 2006; 176(1): 225 - 236. [Abstract] [Full Text] [PDF]
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R. J. DiPaolo, D. D. Glass, K. E. Bijwaard, and E. M. Shevach CD4+CD25+ T Cells Prevent the Development of Organ-Specific Autoimmune Disease by Inhibiting the Differentiation of Autoreactive Effector T Cells J. Immunol., December 1, 2005; 175(11): 7135 - 7142. [Abstract] [Full Text] [PDF]
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A. V. Maker, P. Attia, and S. A. Rosenberg Analysis of the Cellular Mechanism of Antitumor Responses and Autoimmunity in Patients Treated with CTLA-4 Blockade J. Immunol., December 1, 2005; 175(11): 7746 - 7754. [Abstract] [Full Text] [PDF]
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S. Allen, S. Read, R. DiPaolo, R. S. McHugh, E. M. Shevach, P. A. Gleeson, and I. R. van Driel Promiscuous Thymic Expression of an Autoantigen Gene Does Not Result in Negative Selection of Pathogenic T Cells J. Immunol., November 1, 2005; 175(9): 5759 - 5764. [Abstract] [Full Text] [PDF]
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A. Skapenko, J. R. Kalden, P. E. Lipsky, and H. Schulze-Koops The IL-4 Receptor {alpha}-Chain-Binding Cytokines, IL-4 and IL-13, Induce Forkhead Box P3-Expressing CD25+CD4+ Regulatory T Cells from CD25-CD4+ Precursors J. Immunol., November 1, 2005; 175(9): 6107 - 6116. [Abstract] [Full Text] [PDF]
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K. Siegmund, M. Feuerer, C. Siewert, S. Ghani, U. Haubold, A. Dankof, V. Krenn, M. P. Schon, A. Scheffold, J. B. Lowe, et al. Migration matters: regulatory T-cell compartmentalization determines suppressive activity in vivo Blood, November 1, 2005; 106(9): 3097 - 3104. [Abstract] [Full Text] [PDF]
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J. D. Fontenot, J. L. Dooley, A. G. Farr, and A. Y. Rudensky Developmental regulation of Foxp3 expression during ontogeny J. Exp. Med., October 3, 2005; 202(7): 901 - 906. [Abstract] [Full Text] [PDF]
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M. Beyer, M. Kochanek, K. Darabi, A. Popov, M. Jensen, E. Endl, P. A. Knolle, R. K. Thomas, M. von Bergwelt-Baildon, S. Debey, et al. Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine Blood, September 15, 2005; 106(6): 2018 - 2025. [Abstract] [Full Text] [PDF]
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A. M. Marleau and N. Sarvetnick T cell homeostasis in tolerance and immunity J. Leukoc. Biol., September 1, 2005; 78(3): 575 - 584. [Abstract] [Full Text] [PDF]
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F. Aswad, H. Kawamura, and G. Dennert High Sensitivity of CD4+CD25+ Regulatory T Cells to Extracellular Metabolites Nicotinamide Adenine Dinucleotide and ATP: A Role for P2X7 Receptors J. Immunol., September 1, 2005; 175(5): 3075 - 3083. [Abstract] [Full Text] [PDF]
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N. Beyersdorf, S. Gaupp, K. Balbach, J. Schmidt, K. V. Toyka, C.-H. Lin, T. Hanke, T. Hunig, T. Kerkau, and R. Gold Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis J. Exp. Med., August 1, 2005; 202(3): 445 - 455. [Abstract] [Full Text] [PDF]
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L.-F. Lu, D. C. Gondek, Z. A. Scott, and R. J. Noelle NF{kappa}B-Inducing Kinase Deficiency Results in the Development of a Subset of Regulatory T Cells, which Shows a Hyperproliferative Activity upon Glucocorticoid-Induced TNF Receptor Family-Related Gene Stimulation J. Immunol., August 1, 2005; 175(3): 1651 - 1657. [Abstract] [Full Text] [PDF]
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C. Domenig, A. Sanchez-Fueyo, J. Kurtz, S. P. Alexopoulos, C. Mariat, M. Sykes, T. B. Strom, and X. X. Zheng Roles of Deletion and Regulation in Creating Mixed Chimerism and Allograft Tolerance Using a Nonlymphoablative Irradiation-Free Protocol J. Immunol., July 1, 2005; 175(1): 51 - 60. [Abstract] [Full Text] [PDF]
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B. Bienvenu, B. Martin, C. Auffray, C. Cordier, C. Becourt, and B. Lucas Peripheral CD8+CD25+ T Lymphocytes from MHC Class II-Deficient Mice Exhibit Regulatory Activity J. Immunol., July 1, 2005; 175(1): 246 - 253. [Abstract] [Full Text] [PDF]
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L. Pace, C. Pioli, and G. Doria IL-4 Modulation of CD4+CD25+ T Regulatory Cell-Mediated Suppression J. Immunol., June 15, 2005; 174(12): 7645 - 7653. [Abstract] [Full Text] [PDF]
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M. Karim, G. Feng, K. J. Wood, and A. R. Bushell CD25+CD4+ regulatory T cells generated by exposure to a model protein antigen prevent allograft rejection: antigen-specific reactivation in vivo is critical for bystander regulation Blood, June 15, 2005; 105(12): 4871 - 4877. [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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I. W. Nasr, Y. Wang, G. Gao, S. Deng, L. Diggs, D. M. Rothstein, G. Tellides, F. G. Lakkis, and Z. Dai Testicular Immune Privilege Promotes Transplantation Tolerance by Altering the Balance between Memory and Regulatory T Cells J. Immunol., May 15, 2005; 174(10): 6161 - 6168. [Abstract] [Full Text] [PDF]
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S. You, M. Belghith, S. Cobbold, M.-A. Alyanakian, C. Gouarin, S. Barriot, C. Garcia, H. Waldmann, J.-F. Bach, and L. Chatenoud Autoimmune Diabetes Onset Results From Qualitative Rather Than Quantitative Age-Dependent Changes in Pathogenic T-Cells Diabetes, May 1, 2005; 54(5): 1415 - 1422. [Abstract] [Full Text] [PDF]
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A. P. Kohm, J. S. Williams, A. L. Bickford, J. S. McMahon, L. Chatenoud, J.-F. Bach, J. A. Bluestone, and S. D. Miller Treatment with Nonmitogenic Anti-CD3 Monoclonal Antibody Induces CD4+ T Cell Unresponsiveness and Functional Reversal of Established Experimental Autoimmune Encephalomyelitis J. Immunol., April 15, 2005; 174(8): 4525 - 4534. [Abstract] [Full Text] [PDF]
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D. Lundsgaard, T. L. Holm, L. Hornum, and H. Markholst In Vivo Control of Diabetogenic T-Cells by Regulatory CD4+CD25+ T-Cells Expressing Foxp3 Diabetes, April 1, 2005; 54(4): 1040 - 1047. [Abstract] [Full Text] [PDF]
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H. Kataoka, S. Takahashi, K. Takase, S. Yamasaki, T. Yokosuka, T. Koike, and T. Saito CD25+CD4+ regulatory T cells exert in vitro suppressive activity independent of CTLA-4 Int. Immunol., April 1, 2005; 17(4): 421 - 427. [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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P. A. Antony, C. A. Piccirillo, A. Akpinarli, S. E. Finkelstein, P. J. Speiss, D. R. Surman, D. C. Palmer, C.-C. Chan, C. A. Klebanoff, W. W. Overwijk, et al. CD8+ T Cell Immunity Against a Tumor/Self-Antigen Is Augmented by CD4+ T Helper Cells and Hindered by Naturally Occurring T Regulatory Cells J. Immunol., March 1, 2005; 174(5): 2591 - 2601. [Abstract] [Full Text] [PDF]
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T. Alvaro, M. Lejeune, M. T. Salvado, R. Bosch, J. F. Garcia, J. Jaen, A. H. Banham, G. Roncador, C. Montalban, and M. A. Piris Outcome in Hodgkin's Lymphoma Can Be Predicted from the Presence of Accompanying Cytotoxic and Regulatory T Cells Clin. Cancer Res., February 15, 2005; 11(4): 1467 - 1473. [Abstract] [Full Text] [PDF]
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 C Veltkamp, R B Sartor, T Giese, F Autschbach, I Kaden, R Veltkamp, D Rost, B Kallinowski, and W Stremmel Regulatory CD4+CD25+ cells reverse imbalances in the T cell pool of bone marrow transplanted TG{varepsilon}26 mice leading to the prevention of colitis Gut, February 1, 2005; 54(2): 207 - 214. [Abstract] [Full Text] [PDF]
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P. E. Rao, A. L. Petrone, and P. D. Ponath Differentiation and Expansion of T Cells with Regulatory Function from Human Peripheral Lymphocytes by Stimulation in the Presence of TGF-{beta} J. Immunol., February 1, 2005; 174(3): 1446 - 1455. [Abstract] [Full Text] [PDF]
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M.-L. Chen, M. J. Pittet, L. Gorelik, R. A. Flavell, R. Weissleder, H. von Boehmer, and K. Khazaie Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-{beta} signals in vivo PNAS, January 11, 2005; 102(2): 419 - 424. [Abstract] [Full Text] [PDF]
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N. Taylor, K. McConnachie, C. Calder, R. Dawson, A. Dick, J. D. Sedgwick, and J. Liversidge Enhanced Tolerance to Autoimmune Uveitis in CD200-Deficient Mice Correlates with a Pronounced Th2 Switch in Response to Antigen Challenge J. Immunol., January 1, 2005; 174(1): 143 - 154. [Abstract] [Full Text] [PDF]
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H. Sugiyama, R. Gyulai, E. Toichi, E. Garaczi, S. Shimada, S. R. Stevens, T. S. McCormick, and K. D. Cooper Dysfunctional Blood and Target Tissue CD4+CD25high Regulatory T Cells in Psoriasis: Mechanism Underlying Unrestrained Pathogenic Effector T Cell Proliferation J. Immunol., January 1, 2005; 174(1): 164 - 173. [Abstract] [Full Text] [PDF]
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 F. N. Toka, S. Suvas, and B. T. Rouse CD4+ CD25+ T Cells Regulate Vaccine-Generated Primary and Memory CD8+ T-Cell Responses against Herpes Simplex Virus Type 1 J. Virol., December 1, 2004; 78(23): 13082 - 13089. [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. A. Salam, K. Matin, N. Matsumoto, Y. Tsuha, N. Hanada, and H. Senpuku E2f1 Mutation Induces Early Onset of Diabetes and Sjogren's Syndrome in Nonobese Diabetic Mice J. Immunol., October 15, 2004; 173(8): 4908 - 4918. [Abstract] [Full Text] [PDF]
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H. C. Dujardin, O. Burlen-Defranoux, L. Boucontet, P. Vieira, A. Cumano, and A. Bandeira Regulatory potential and control of Foxp3 expression in newborn CD4+ T cells PNAS, October 5, 2004; 101(40): 14473 - 14478. [Abstract] [Full Text] [PDF]
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J. Kipnis, H. Avidan, R. R. Caspi, and M. Schwartz Dual effect of CD4+CD25+ regulatory T cells in neurodegeneration: A dialogue with microglia PNAS, October 5, 2004; 101(suppl_2): 14663 - 14669. [Abstract] [Full Text] [PDF]
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Y. Miura, C. J. Thoburn, E. C. Bright, M. L. Phelps, T. Shin, E. C. Matsui, W. H. Matsui, S. Arai, E. J. Fuchs, G. B. Vogelsang, et al. Association of Foxp3 regulatory gene expression with graft-versus-host disease Blood, October 1, 2004; 104(7): 2187 - 2193. [Abstract] [Full Text] [PDF]
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N. Sarween, A. Chodos, C. Raykundalia, M. Khan, A. K. Abbas, and L. S. K. Walker CD4+CD25+ Cells Controlling a Pathogenic CD4 Response Inhibit Cytokine Differentiation, CXCR-3 Expression, and Tissue Invasion J. Immunol., September 1, 2004; 173(5): 2942 - 2951. [Abstract] [Full Text] [PDF]
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B. E. Anderson, J. M. McNiff, C. Matte, I. Athanasiadis, W. D. Shlomchik, and M. J. Shlomchik Recipient CD4+ T cells that survive irradiation regulate chronic graft-versus-host disease Blood, September 1, 2004; 104(5): 1565 - 1573. [Abstract] [Full Text] [PDF]
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B. T. Rouse and S. Suvas Regulatory Cells and Infectious Agents: Detentes Cordiale and Contraire J. Immunol., August 15, 2004; 173(4): 2211 - 2215. [Abstract] [Full Text] [PDF]
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A. L. Kinter, M. Hennessey, A. Bell, S. Kern, Y. Lin, M. Daucher, M. Planta, M. McGlaughlin, R. Jackson, S. F. Ziegler, et al. CD25+CD4+ Regulatory T Cells from the Peripheral Blood of Asymptomatic HIV-infected Individuals Regulate CD4+ and CD8+ HIV-specific T Cell Immune Responses In Vitro and Are Associated with Favorable Clinical Markers of Disease Status J. Exp. Med., August 2, 2004; 200(3): 331 - 343. [Abstract] [Full Text] [PDF]
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C. Baecher-Allan and D. A. Hafler Suppressor T Cells in Human Diseases J. Exp. Med., August 2, 2004; 200(3): 273 - 276. [Abstract] [Full Text] [PDF]
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). The mice with less severe
infiltration have lower Ab titer (1:50–1:500, •), and Ab-negative
mice did not develop gastritis (
). Control nu/nu mice in
our colony never showed any signs of gastritis (data not shown).
B, Gastric LN cells from nu/nu mice with
pathologic evidence of gastritis proliferate in response to H/K ATPase
(
), with membranes from insect
cells transfected with rat H/K ATPase 
), or
with control insect cell membranes (
); [3H]TdR
incorporation was determined after 96 h of culture.
