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*
Institut National de la Santé et de la Recherche Médicale Unité 343 Hopital de l’Archet, Nice, France; and
DNAX Research Institute, Palo Alto, CA 94304
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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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20–25%
of the population is affected. It represents one of the most common
examples of in vivo activation of inappropriate pattern of Th2-type
cytokines synthesis (1).
Th2 responses are mediated by CD4+ T cells that
secrete cytokines, such as IL-4, IL-5, and IL-13, which are known to
play a central role in allergic responses (2, 3, 4). In
contrast to healthy subjects, allergic patients develop specific IgE
directed against sensitizing allergens that play a key role in the
physiopathology of allergic diseases (5). Induction of IgE
switching requires two primary signals. The first one, given by IL-4 or
IL-13, induces the expression of the sterile 
transcript
(6, 7, 8). The second one, provided by the triggering of CD40
ligand, induces the expression of the mature transcript encoding
for IgE (9, 10). Several cytokines modulate IL-4-dependent
IgE production. IFN-
, IFN-
, TGF-ß, and IL-12 have inhibitory
effects, whereas IL-2, IL-5, IL-6, and TNF- enhance IL-4-induced IgE
synthesis.
IL-10 is a cytokine produced by numerous cell types, including activated T cells, mast cells, and macrophages. By blocking Ag-presenting capacities of monocytes/macrophages, IL-10 plays a major role in suppressing immune and inflammatory responses (11). IL-10 also acts on human B cells activated by anti-CD40 mAb by enhancing the switching to IgA, IgG1, and IgG3 isotypes (12, 13), the short-term proliferation (14), and the differentiation of B-cells into Ig-secreting plasma cells (15). However, IL-10 specifically decreases IgE production by IL-4-stimulated PBMC in vitro (16).
We have recently shown that both human and mouse CD4+ T cells repeatedly stimulated in the presence of IL-10 differentiate into a new subset of CD4+ T cells different from the classical Th1 and Th2 T cell clones (17). These cells, termed T regulatory 1 (Tr1)3 have a poor proliferative response and secrete no IL-2 or IL-4, but produce high levels of IL-10 and inhibit the proliferative response of bystander cells both in vitro and in vivo (17). Using OVA-immunized BALB/c mice in the presence of alum that generate a Th2-type response characterized by substantial IL-4 and IL-5 production, we examined the impact of Tr1 cells in the regulation of IgE and CD4+ T cells responses to OVA. These experiments could also give evidence of potential helper function of Tr1 cells on B cell activation and differentiation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/cAnN mice were obtained from CERJ (Le Genest Saint Isle, France), and homozygous DO11-10 mice were a generous gift from Dr. A. O’Garra (DNAX Research Institute, Palo Alto, CA). All mice were raised free of common mouse pathogen conditions in our animal facility. They were all female mice, 6- to 8-wk-old at the beginning of each experiment.
Cytokine ELISA
Sandwich ELISAs were used to measure IL-4, IL-5, IL-10, and
IFN- as previously described (18). In brief, ELISA
plates were coated with the appropriate anti-cytokine Abs (11B11,
TRFK4, 2A5, and XGM1.2 for IL-4, IL-5, IL-10, and IFN-,
respectively) and incubated at 4°C overnight. After incubation,
plates were blocked for 30 min at room temperature by adding 150 µl
of 20% FCS/PBS containing 0.04% Tween 20 to each well. Supernatants
from in vitro-stimulated purified splenocytes were diluted in 5% FCS
Yssel’s medium and added at a volume of 50 µl/well. Plates were
incubated overnight at 4°C then washed and the second-step Ab (24G2,
TRFK5, SXC1, and R4-6A2 for IL-4, IL-5, IL-10, and IFN-,
respectively) was added at 50 µl/well. Plates were incubated for
1 h at room temperature then washed and the enzyme conjugate was
added to each well. Plates remained at room temperature for 1 h,
after which they were washed and 100 µl/well of substrate containing
1 mg/ml 2,2'-azinobis(3-ethylbenzthiazolinesulfonic acid) (Sigma, St.
Louis, MO), 0.0003% H2O2
in Na2HPO4, and 0.05 M
citric acid was added. After the substrate was developed, applying 50
µl of 0.2 M citric acid solution to each well stopped the reaction.
The plates were read on an ELISA reader (Labsystems iEMS reader,
Helsinki, Finland). Abs for ELISAs were purified from serum-free
hybridoma supernatants as previously described (18).
Analysis of OVA-specific serum IgE
OVA-specific serum IgE was determined using a two-step sandwich ELISA without depleting for IgG as described (19). The coating Ab was a monoclonal anti-IgE Ab called EM95. The second step was a digoxigenin-coupled OVA that was prepared according to the manufacturer’s instructions (Boehringer Mannheim GmbH, Mannheim, Germany). In brief, plates were coated with 2 µg/ml of EM95 and incubated overnight at 4°C. The serum samples were added and, subsequently, the digoxigenin-coupled OVA was added to the wells. Antidigoxigenin-Fab coupled to peroxidase (Boehringer Mannheim) were added. As described above, after 1 h of incubation, 0.1 ml of substrate was added to each well.
Analysis of OVA-specific IgG1 and IgG2a
ELISA plates were coated overnight at 4°C with 10 µg/ml OVA in PBS. The detecting Ab for IgG1 that was used at 0.5 µg/ml was a biotinylated rabbit anti IgG1. The detecting Ab for the IgG2a was a rabbit anti-IgG2a coupled with the nitroiodophenyl hapten. After incubation and washing, peroxidase-conjugated streptavidin was added to the wells of the IgG1 ELISA. The nitroiodophenyl-labeled anti-IgG2a was revealed with a HRP conjugate of a rat monoclonal anti-nitroiodophenyl Ab. Finally, plates were developed as described above. Standards for OVA-specific IgG1 were pooled from sera from hyperimmunized BALB/c mice. The concentration of OVA-specific IgG1 was estimated by comparison to an IgG1 standard run in parallel on anti-IgG1-coated plates. This method was also used for the quantification of OVA-specific IgE and IgG2a in the ELISA.
Cell lines, culture, and reagents
All assays were conducted in Yssel’s medium (20) supplemented with 10% FCS. CD4+ T cells were purified from the lymph nodes of mice by negative depletion using anti-B220, anti-Mac-1, anti-CD8, and KJ1-26 mAbs (PharMingen, San Diego, CA) and sheep anti-rat-coated Dynabeads (Dynal, Oslo, Norway). In brief, cells were incubated with the different Abs (10 µg/ml) for 30 min at 4°C; after washing, 500 µl of beads for 5 x 107 cells were added for 30 min at 4°C. Cells were negatively purified upon application of a magnetic field. The T cell clones were obtained from DO11-10 mice after in vitro differentiation as previously described (21). Naive (MEL-14bright) CD4+, KJ1-26+ cells were stimulated repeatedly for 3 wk with OVA peptide 323–339 in the presence of IL-4 and anti-IL-12, IL-12 and anti-IL-4, or IL-10 for Th2, Th1, or Tr1 cells, respectively. The populations obtained were cloned at 1 cell/well by cytofluorometry (FACSvantage SE; Becton Dickinson, Mountain View, CA) and stimulated with irradiated splenocytes (4500 rad) and OVA peptide. Clones were then expanded and analyzed for cytokine secretion after activation with APCs and OVA peptide. Selected clones were then cultured with stimulation with irradiated splenocytes and OVA peptide every 2 wk and further expanded with 10 ng/ml IL-2 (R&D Systems, Minneapolis, MN). T cell clones were used at least 10 days after the last stimulation. Several T cell clones were used. A-10-9 and A-10-11 were previously described (17), Nice-1 and Nice-2 were cloned after in vitro differentiation of KJ1-26+ cells in the presence of IL-10 and selected based on proliferation and cytokine secretion. D4-6, D4-15, and D4-19 were Th2 T cell clones isolated after differentiation of KJ1-26+ cells in the presence of IL-4 and anti-IL-12. A-7 and A-21 were Th1 T cell clones isolated after differentiation of KJ1-26+ cells in the presence of IL-12 and anti-IL-4 as described (17).
Anti-IL-10 receptor-blocking mAbs (1B1.2) were kindly provided by K. Moore (DNAX Research Institute, Palo Alto, CA). Abs were injected i.p. at day 0 (1 mg/mouse), and injection was repeated every week at 0.5 mg/mouse.
To measure cytokines released by CD4+ T cells contained in mesenteric lymph nodes, purified cells were stimulated in 1-ml cultures. The culture medium consisted of Yssel’s medium with 10% heat-inactivated FCS (Roche, Meylan, France), 0.05 mM 2-ME (Sigma), and penicillin/streptomycin (Life Technologies, Gaithersburg, MD). Purified CD4+ T cells were stimulated at 2 x 106 cells/ml in culture medium containing 0.25 mg/ml OVA and irradiated splenocytes (5 x 106 cells/ml). The supernatant was harvested at 48 h.
Immunization and adoptive transfer of OVA-specific CD4+ T cell clones
Mice were immunized with 10 µg/mouse of OVA with alum (both from Sigma) injected i.p. at day 0 and day 21. OVA-specific T cell clones (106 cells/mouse) were injected i.p. 2 h before OVA injection at day 0 and day 21.
Flow cytometry
For analysis, splenocytes were stained with FITC- or PE-conjugated mAbs (PharMingen). Flow cytometry analysis was performed on a FACScan flow cytometer (Becton Dickinson) and analyzed with the CellQuest software.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To evaluate the capacity of Ag-specific Tr1 clones to either
promote B cell help or inhibit a Th2 response, OVA-specific T cell
clones were transferred into BALB/c mice 2 h before OVA (alum)
immunization. In contrast to the situation where Th1 and Th2 T cell
clones were transferred, no helper activity on Ig secretion was
detected after injection of Tr1 T cell clones. Instead, the
OVA-specific IgE response was inhibited by 90% by the transferred Tr1
clones, whereas OVA-specific IgG1 and IgG2a responses were not
inhibited (Fig. 1
). This specific effect
of Tr1 clones on IgE production was completely reversed after injection
of blocking anti-IL-10R Abs, confirming the importance of this
cytokine in the regulatory effect of Tr1 clones (17). In
contrast to Tr1 clones, no modification in IgE, IgG1, and IgG2a
responses was observed after the transfer of an OVA-specific Th1 clone,
and a slight enhancement of the specific IgE response was observed
after transfer of an OVA-specific Th2-specific clone (Fig. 1).
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We analyzed the effect of Tr1 clones on the activation of
Ag-specific T cells in vivo by testing the recall in vitro
proliferative response to OVA of CD4+ T cells
previously depleted of the injected clones by using the
anti-clonotype Ab KJ1-26. Injection of Tr1 cells resulted in a
decreased recall proliferative response to OVA of
CD4+ T cells isolated from mesenteric lymph
nodes, whereas injection of a Th1- or a Th2-specific clone resulted in
an enhancement in the in vivo priming for Ag-specific cells (Fig. 2). Again, addition of IL-10R blocking
Abs reverted the effect of Tr1 cells on the priming of OVA-specific T
cells in vivo (Fig. 2).
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). Addition of a Tr1 clone inhibited the
number of activated (CD4+,
CD25+, KJ1-26-) T cells
present in mesenteric lymph nodes, whereas addition of Th1 or Th2
OVA-specific clones slightly enhanced the number of activated T
cells.
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To determine the cytokine profile of OVA-specific host
CD4+ T cells induced by immunization of mice
receiving different types of Ag-specific T cell clones, lymph nodes
were taken 7 days after the second immunization with alum and OVA.
Draining lymph nodes’ T cells were depleted of
KJ1-26+ T cells, restimulated in vitro, and their
supernatants were assayed for cytokines. Mice immunized with OVA in
alum mounted a strong Th2 response as indicated by the significant
levels of IL-4, IL-5, and IL-10, and undetectable levels of IFN-
(Table I). The presence of Tr1 clones at
the time of immunization dramatically inhibited the differentiation of
IL-4-secreting cells and promoted the differentiation of a Tr1 cell
type population secreting no IL-4, high IL-10, and some IL-5 (Table I).
The presence of a Th2 clone at the time of immunization enhanced the
priming of naive CD4 T cells toward a Th2-type response with increased
levels of secreted IL-4 and IL-5. Finally, the presence of a Th1 clone
reduced the amounts of Th2-type cytokines (IL-4, IL-5, and IL-10)
secreted by primed CD4+ T cells, but enhanced the
differentiation of IFN--secreting Ag-specific T cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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More importantly, Tr1 cells were shown to be immune suppressive in vivo in a typical Th1-mediated inflammation. Indeed, a colitis induced in scid mice by transfer of CD45RBhighCD4+ T cells was prevented by cotransfer of murine OVA-specific Tr1 clones. Immune suppression was dependent on Ag-induced activation of Tr1 cells in vivo as these cells only inhibited colitis in recipients that received OVA in their drinking water. Similar to in vitro experiments, we recently observed that in vivo suppression mediated by Tr1 clones was completely abrogated when mice were treated with anti-IL-10 receptor Abs (F. Cottrez and H. Groux, manuscript in preparation), confirming in this different model, the importance of IL-10 in the function of Tr1 clones.
In this study, the role of Ag-specific Tr1 cells in modulating Th2 responses in vivo was compared with Th1 and Th2 clones expressing the same specificity. Preliminary experiments using Th1 and Th2 clones have shown that injection of the T cell clones 2 h before immunization allows the analysis of both stimulatory and inhibitory effects of the T cells on Ig secretion. Intraperitoneal injection of OVA in alum induced OVA-specific IgE in naive BALB/c mice, but not in mice previously transferred with OVA-specific Tr1 clones. The same clones did not suppress OVA-specific IgG1 and IgG2a responses. No inhibition of IgE synthesis was observed in mice transferred with a Th1 clone, whereas a slight enhancement in IgE levels was observed in mice treated with an OVA-specific Th2 clone, as expected. The inhibition of IgE synthesis induced by Tr1 clones was mediated by their capacity to secrete high levels of IL-10 as treatment of mice with anti-IL-10 receptor Abs completely reverted the amounts of IgE detected in the serum of immunized mice.
IL-10 was originally described as a mouse Th2 cell factor, inhibiting
cytokine synthesis by Th1 cells (22). However, increasing
evidence suggest that IL-10 also acts as an inhibitor of Th2 cell
responses both in vitro and in vivo (23, 24, 25). In
particular, IL-10 was found to down-regulate IL-5 production by
human resting T cells and in human Th0 and Th2 clones (25, 26). The inhibitory action of IL-10 on IL-5 synthesis was
confirmed in a murine model of allergic eosinophilic peritonitis and
airway eosinophilia in which IL-10 administration suppressed both IL-5
production and eosinophil recruitment (24, 25). Finally,
in mice, IL-10 administration before allergen treatment induces
Ag-specific tolerance (27). We confirm in this report the
direct effect of IL-10 in specifically inhibiting IgE synthesis in
vivo. It has been previously reported that IL-10 decreases
transcript expression and IgE production by IL-4- or IL-13-stimulated
PBMC (16, 28). However, the inhibitory effect of Tr1
clones seems to be more profound than a specific inhibition at the B
cell level.
Indeed, direct examination of the OVA-specific T cell recall response in vitro revealed that Tr1-treated mice did not develop significant CD4+ T cell responses, suggesting that specific loss of IgE responses in Tr1-treated mice reflects a more fundamental inhibition in the activation of OVA-specific T cells by the regulatory T cells. Similar specific inhibition of IgE responses in vivo and induction of anergy in CD4+ T cells has been reported in different human (29) and mouse (19, 30) models of tolerance induction. In humans, specific immunotherapy is an efficient treatment for allergic diseases and is used most effectively in allergic reactions to insect venom and allergic rhinitis (31). It has recently been shown that administration of high allergen doses, as applied in immunotherapy, enhances endogenous production of IL-10 in specific T cells similar to Tr1 clones (29). Similarly, we recently demonstrated that exposure to inhaled OVA induced a state of unresponsiveness of CD4+ T cells that results in a prolonged loss of IgE and eosinophil responses to subsequent challenges (19). Whether this T cell unresponsiveness reflects the action of a regulatory population has not yet been determined by us; however, previous experiments with this model in both rats and mice suggest that an active suppression is involved (32, 33).
In a similar model, it has been suggested that the
TCR-/
+ T cells are the principal mediators
of IgE suppression (33). Adoptive transfer of
TCR-/+ T cells from aerosol OVA-primed mice
suppressed OVA-specific IgE secretion in mice immunized with OVA
(alum). However, our recent results showing that mice deficient in
TCR-/+ T cells have the same degree of
IgE-specific unresponsiveness after aerosol priming and immunization
with OVA argue against a unique role of these cells in establishing IgE
unresponsiveness (19). The same group (34)
and others (35) have also shown that
CD8+ T cells, through the secretion of IFN-,
were also important in suppressing IgE response. However, injection of
Th1 T cell clones secreting IFN- did not result in inhibition of IgE
secretion (Fig. 1
). Moreover, we have recently shown in the model
described above using aerosol-primed mice depleted of
CD8+ T cells with specific Abs or mice deficient
for the ß2-microglobulin molecule that
CD8+ T cells do not have a major role in
aerosol-induced IgE unresponsiveness to soluble protein Ag. Our
experiments do not rule out the possibility that
CD8+ T cells could transfer an IgE-specific
suppression, but simply show that CD8+ T cells
are not required to suppress IgE synthesis as previously described
(36).
Similar analysis has been done to study the unresponsiveness that occurs after oral Ag ingestion. Investigators have shown that the feeding of mice transgenic for OVA-specific TCR with high doses of OVA can inhibit airway eosinophilic inflammation induced by intratracheally administered OVA. This inhibitory effect was adoptively transferred by splenic CD4+ T cells, demonstrating that it is an active mechanism (37). Overall, there are clear similarities between the results obtained when tolerance is induced by multiple Ag challenges or when mice are treated with Tr1 clones, suggesting that tolerance induction in these models operates through the differentiation of Tr1-type response.
In summary, the data presented above demonstrate that Tr1 clones actively modulate a Th2-type response in vitro through the secretion of IL-10, thus strengthening the role of IL-10 as a general immunomodulator of immune responses. Improved knowledge of the differentiation mechanisms and effector function of Tr1 cells should provide a crucial insight into their role in the allergic response in vivo and help us to better understand the disregulation of the immune response resulting in allergic disorders.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Hervé Groux, Institut National de la Santé et de la Recherche Médicale Unité 343 Hopital de l’Archet, Route de Saint Antoine de Ginestiere, 06000 Nice, France.
3 Abbreviation used in this paper: Tr1, T regulatory 1.
Received for publication December 16, 1999. Accepted for publication August 1, 2000.
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transcripts in human B cells induced by interleukin 4 to switch to IgE production. J. Exp. Med. 172:463./+ T cells or interferon (IFN)- in a murine model of allergen sensitization. J. Exp. Med. 187:721. selectively inhibits the production of interleukin-5 by human CD4+ T cells. J. Clin. Invest. 97:309.[Medline]
T cells down-regulate primary IgE responses in rats to inhaled soluble protein antigens. J. Immunol. 154:4390.[Abstract]
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G. Prioult, S. Pecquet, and I. Fliss Stimulation of Interleukin-10 Production by Acidic {beta}-Lactoglobulin-Derived Peptides Hydrolyzed with Lactobacillus paracasei NCC2461 Peptidases Clin. Vaccine Immunol., March 1, 2004; 11(2): 266 - 271. [Abstract] [Full Text] [PDF]
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 H. Hammad, H. J. de Heer, T. Soullie, V. Angeli, F. Trottein, H. C. Hoogsteden, and B. N. Lambrecht Activation of Peroxisome Proliferator-Activated Receptor-{gamma} in Dendritic Cells Inhibits the Development of Eosinophilic Airway Inflammation in a Mouse Model of Asthma Am. J. Pathol., January 1, 2004; 164(1): 263 - 271. [Abstract] [Full Text] [PDF]
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A. Gojova, V. Brun, B. Esposito, F. Cottrez, P. Gourdy, P. Ardouin, A. Tedgui, Z. Mallat, and H. Groux Specific abrogation of transforming growth factor-{beta} signaling in T cells alters atherosclerotic lesion size and composition in mice Blood, December 1, 2003; 102(12): 4052 - 4058. [Abstract] [Full Text] [PDF]
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A. Foussat, F. Cottrez, V. Brun, N. Fournier, J.-P. Breittmayer, and H. Groux A Comparative Study between T Regulatory Type 1 and CD4+CD25+ T Cells in the Control of Inflammation J. Immunol., November 15, 2003; 171(10): 5018 - 5026. [Abstract] [Full Text] [PDF]
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Z. Guo, E. Kavanagh, Y. Zang, S. M. Dolan, S. J. Kriynovich, J. A. Mannick, and J. A. Lederer Burn Injury Promotes Antigen-Driven Th2-Type Responses In Vivo J. Immunol., October 15, 2003; 171(8): 3983 - 3990. [Abstract] [Full Text] [PDF]
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 Z. Mallat, A. Gojova, V. Brun, B. Esposito, N. Fournier, F. Cottrez, A. Tedgui, and H. Groux Induction of a Regulatory T Cell Type 1 Response Reduces the Development of Atherosclerosis in Apolipoprotein E-Knockout Mice Circulation, September 9, 2003; 108(10): 1232 - 1237. [Abstract] [Full Text] [PDF]
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S. Sehra, G. Pynaert, K. Tournoy, A. Haegeman, P. Matthys, Y. Tagawa, R. Pauwels, and J. Grooten Airway IgG Counteracts Specific and Bystander Allergen-Triggered Pulmonary Inflammation by a Mechanism Dependent on Fc{gamma}R and IFN-{gamma} J. Immunol., August 15, 2003; 171(4): 2080 - 2089. [Abstract] [Full Text] [PDF]
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C. Chen, W.-H. Lee, P. Yun, P. Snow, and C.-P. Liu Induction of Autoantigen-Specific Th2 and Tr1 Regulatory T Cells and Modulation of Autoimmune Diabetes J. Immunol., July 15, 2003; 171(2): 733 - 744. [Abstract] [Full Text] [PDF]
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 K. Asadullah, W. Sterry, and H. D. Volk Interleukin-10 Therapy--Review of a New Approach Pharmacol. Rev., June 1, 2003; 55(2): 241 - 269. [Abstract] [Full Text] [PDF]
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C. Mottet, H. H. Uhlig, and F. Powrie Cutting Edge: Cure of Colitis by CD4+CD25+ Regulatory T Cells J. Immunol., April 15, 2003; 170(8): 3939 - 3943. [Abstract] [Full Text] [PDF]
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M. Taneichi, S. Naito, H. Kato, Y. Tanaka, M. Mori, Y. Nakano, H. Yamamura, H. Ishida, K. Komuro, and T. Uchida T Cell-Independent Regulation of IgE Antibody Production Induced by Surface-Linked Liposomal Antigen J. Immunol., October 15, 2002; 169(8): 4246 - 4252. [Abstract] [Full Text] [PDF]
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F. J. Quintana, P. Carmi, F. Mor, and I. R. Cohen Inhibition of Adjuvant Arthritis by a DNA Vaccine Encoding Human Heat Shock Protein 60 J. Immunol., September 15, 2002; 169(6): 3422 - 3428. [Abstract] [Full Text] [PDF]
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 K. Asadullah, W. Sterry, and H.-D. Volk Analysis of Cytokine Expression in Dermatology Arch Dermatol, September 1, 2002; 138(9): 1189 - 1196. [Abstract] [Full Text] [PDF]
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P. Hoffmann, J. Ermann, M. Edinger, C. G. Fathman, and S. Strober Donor-type CD4+CD25+ Regulatory T Cells Suppress Lethal Acute Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation J. Exp. Med., August 5, 2002; 196(3): 389 - 399. [Abstract] [Full Text] [PDF]
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 E. M. Janssen, M. H. M. Wauben, F. P. Nijkamp, W. van Eden, and A. J. M. van Oosterhout Immunomodulatory Effects of Antigen-Pulsed Macrophages in a Murine Model of Allergic Asthma Am. J. Respir. Cell Mol. Biol., August 1, 2002; 27(2): 257 - 264. [Abstract] [Full Text] [PDF]
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K. Steinbrink, E. Graulich, S. Kubsch, J. Knop, and A. H. Enk CD4+ and CD8+ anergic T cells induced by interleukin-10-treated human dendritic cells display antigen-specific suppressor activity Blood, April 1, 2002; 99(7): 2468 - 2476. [Abstract] [Full Text] [PDF]
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P. McGuirk, C. McCann, and K. H.G. Mills Pathogen-specific T Regulatory 1 Cells Induced in the Respiratory Tract by a Bacterial Molecule that Stimulates Interleukin 10 Production by Dendritic Cells: A Novel Strategy for Evasion of Protective T Helper Type 1 Responses by Bordetella pertussis J. Exp. Med., January 22, 2002; 195(2): 221 - 231. [Abstract] [Full Text] [PDF]
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M. F. Lipscomb and B. J. Masten Dendritic Cells: Immune Regulators in Health and Disease Physiol Rev, January 1, 2002; 82(1): 97 - 130. [Abstract] [Full Text] [PDF]
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M. A. C. de Lafaille, S. Muriglan, M.-J. Sunshine, Y. Lei, N. Kutchukhidze, G. C. Furtado, A. K. Wensky, D. Olivares-Villagomez, and J. J. Lafaille Hyper Immunoglobulin E Response in Mice with Monoclonal Populations of B and T Lymphocytes"" J. Exp. Med., November 5, 2001; 194(9): 1349 - 1360. [Abstract] [Full Text] [PDF]
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A. Wakkach, F. Cottrez, and H. Groux Differentiation of Regulatory T Cells 1 Is Induced by CD2 Costimulation J. Immunol., September 15, 2001; 167(6): 3107 - 3113. [Abstract] [Full Text] [PDF]
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M. K. Levings, R. Sangregorio, and M.-G. Roncarolo Human Cd25+Cd4+ T Regulatory Cells Suppress Naive and Memory T Cell Proliferation and Can Be Expanded in Vitro without Loss of Function J. Exp. Med., June 4, 2001; 193(11): 1295 - 1302. [Abstract] [Full Text] [PDF]
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M.-G. Roncarolo, M. K. Levings, and C. Traversari Differentiation of T Regulatory Cells by Immature Dendritic Cells J. Exp. Med., January 15, 2001; 193(2): f5 - f10. [Full Text] [PDF]
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) or culture medium alone (
) in the presence of
irradiated splenocytes. One group of mice transferred with the Tr1
clone was treated with anti-IL-10 receptor Abs (1 mg/mouse at 1-wk
intervals starting at day 0) (
). Results shown are mean ± SD
cpm of triplicate cultures from the pooled cells of five mice.