IL-22, in contrast to IL-10, does not induce Ig production, due to absence of a functional IL-22 receptor on activated human B cells
Sandrine Lécart1,
Frank Morel2,
Nelly Noraz3,
Jérôme Pène1,
Martine Garcia2,
Katia Boniface2,
Jean-Claude Lecron2 and
Hans Yssel1
1 INSRM U454, CHU Arnaud de Villeneuve, 371, Avenue Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France 2 IBMIG, CNRS FRE 2224, 40 Avenue du Recteur Pineau, 86022 Poitiers Cedex, France 3 Institut Génétique Moléculaire, UMR 5535, 1919 Route de Mende, 34033 Montpellier Cedex 1, Montpellier, France
The first two authors contributed equally to this work
Correspondence to: H. Yssel; E-mail: yssel{at}montp.inserm.fr
Transmitting editor: J. Borst
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Abstract
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IL-22 is an IL-10 homologue that binds to and signals via the class II cytokine receptor (R) heterodimer IL-22RA1/CFR2-4 (IL-10R2), the latter chain being part of the IL-10R complex. Here, we report that, despite its structural similarity with IL-10, as well as its use of the common IL-10R2 chain, IL-22, in contrast to IL-10, is unable to induce Ig production by activated human B cells. Whereas culture of anti-CD40 mAb-stimulated splenic or tonsillar B cells in the presence of rIL-10 resulted in the production of IgG, IgG1, IgG3 and IgA, rIL-22, at concentrations ranging from 4 to 100 ng/ml, did not induce the production of any of these isotypes. Moreover, unlike rIL-10 which enhanced rIL-4-induced IgG4 and IgE production, rIL-22 was ineffective. Although activated B cells expressed transcripts for a soluble IL-22-binding protein (IL-22RA2), no mRNA for a transmembrane IL-22R (IL-22RA1) could be detected. The latter result was confirmed by the demonstration that rIL-22 failed to induce activation of STAT-3 and -5 in resting or activated B cells. Together, these data show that IL-22, in contrast to its homologue IL-10, is not involved in the immunological activity of B cells, which is due to the absence of a functional IL-22R at the surface of these cells.
Keywords: B cell, ELISA, IL-10, IL-12, signal transduction, Western blotting
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Introduction
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IL-22 is a cytokine with significant homology to IL-10 that has recently been identified in humans (1) as well as in mice (2). Mouse IL-22 is also known as IL-10-related T cell-derived inducible factor (IL-TIF-
). The human IL-22 cDNA encodes a protein of 179 amino acids that has 25% identity to human IL-10. The relationship between IL-10 and IL-22 is furthermore underscored by the observation that IL-22 binds and signals through a receptor (R) complex that is composed of the IL-22RA1 chain (CRF-9), a novel member of the class II cytokine receptor family (1), and the IL-10R2 chain (1,3,4). Originally described as an IL-9-inducible cytokine, IL-TIF is produced by activated T cells and mast cells (2). Injection of lipopolysaccharide into mice induces IL-22 transcription and production by hepatocytes, resulting in a rapid increase in the production of acute-phase reactants in the liver, suggesting that IL-22 might contribute to inflammatory responses in vivo (2). However, apart from the observation that human IL-22 has slight inhibitory effects on the production of IL-4 by Th2 cells (1), at present little is known about its functional activity on other cell types of the immune system.
During antigen-induced immune responses, human B cells switch from the production of IgM/IgD to that of IgG14, IgA12 or IgE, a process that is dependent on CD40 engagement, as well as on the presence of cytokines which are able to induce B cells to the production of specific isotypes. Human IL-10 induces the synthesis of IgM, IgG1 and IgG3, but not IgG2 or IgG4, by anti-CD40 mAb-activated naive, surface IgD+ (sIgD+) tonsillar B cells (5,6). Furthermore, such B cells, activated with an anti-CD40 mAb, can be induced to produce IgA, following their culture in the presence of both transforming growth factor-ß and IL-10 (7). Although IL-10 is not a switch factor for the production of IgG4, it increases IgG4 production by potentiating IL-4-induced IgG4 switching, as well as by enhancing the growth and/or differentiation of B cells that are already committed to the production of IgG4 (8).
Because of its structural homology with IL-10, we have studied the capacity of human rIL-22 to induce Ig production by human B cells. In the present study we show that rIL-22, unlike rIL-10, is ineffective in this process and that it is unable to induce the production of Ig by anti-CD40 mAb-activated purified splenic or tonsillar B cells, which is due to the lack of expression of a functional receptor for IL-22 on these cells.
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Methods
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Cytokines
The following human recombinant cytokines were used in this study: rIL-4, rIFN-
and rIL-10, which were generous gifts from Drs N. Nagabushan (DNAX, Palo Alto, CA) and Francine Brière (Schering-Plough, Dardilly, France) respectively, and rIL-22, a generous gift of Austin Gurney, Genentech, South San Francisco, CA (1).
Cells and culture conditions
Highly purified B cells were obtained from human tonsil or spleen mononuclear cells as follows. Pieces of spleen or tonsil were gently pressed through a 100 µm cell strainer followed by centrifugation of the cell suspension over Ficoll-Hypaque. CD19+ B cells were isolated by positive selection using specific mAb-coated magnetic beads and a preparative magnetic cell sorter (Miltenyi, Bergisch Gladbach, Germany), according to the experimental procedure recommended by the manufacturer. Purity of the selected B cell populations was analyzed by immunostaining and flow cytometry (FACScan; Becton Dickinson, San Jose, CA). Only B cell populations >98% CD19+ were used in the experiments.
For induction of Ig, 2 x 105 CD19+ spleen- or tonsil-derived B lymphocytes were cultured with various combinations of cytokines, as indicated in the text or figures, in the presence or absence of 1 µg/ml of the anti-CD40 mAb 89 (9) (a kind gift of Dr Francine Brière) in flat-bottom 96-well culture plates in IMDM (Gibco/Life Technologies, Cergy Pontoise, France), supplemented with 10% FCS in sextuplate in a final volume of 200 µl. After 12 days of incubation at 37°C and 5% CO2, culture supernatants were collected, spun for 3 min at 270 g to remove residual B cells, aliquotted and stored at 80°C prior to Ig measurements. The hepatocyte cell line HepG2 was used as a control cell line for the detection of mRNA specific for cell surface IL-22RA1 or the IL-22-binding protein, IL-22RA2, as well as for Western blot analysis of STAT phosphorylation.
Measurement of Ig production
Total IgG, IgG1, IgG3, IgG4, total IgA and IgE secretion was determined by isotype-specific ELISA, as described previously (10,11). Briefly, 96-well ELISA plates (Nunc, Roskilde, Denmark) were coated at 4°C for 18 h with antibody or anti-serum directed against IgG (Dade Behring, Paris, France), IgG1, IgG3 (Oxoid/Skybio, Bedfordshire, UK), IgG4 (Southern Biotechnology, Birmingham AL), IgA (BD Biosciences/PharMingen, Le Pont de Claix, France) and IgE (Dako, Trappes, France) raised against each isotype in 125 mM carbonate buffer, pH 9.6. The plates were washed 3 times with PBS containing 0.05% Tween 20 and saturated at room temperature for 1 h with 0.1% BSA (Sigma-Aldrich, St Louis, MO) in PBS. Then 50 µl of culture supernatant was added to the wells and incubated for 18 h at 4°C. After washing with Tween 20 buffer anti-IgG, IgA (Dako), IgG1 and IgG3 (Sigma-Aldrich) antibodies, conjugated to peroxidase and diluted in Tween 20 buffer, were added and the plates were incubated at room temperature for 1 h. IgG4 and IgE measurements were carried out in a two-step assay, by incubating the wells with a purified anti-IgG4 mAb (Bionostics, Devens, MA) or the anti-IgE mAb I-27 (11) for 2 h at room temperature, followed by an incubation with a goat anti-mouse IgG antibody (Dako) for 1 h. After washing, bound enzyme activity was measured using 1 mg/ml of 2'2-azinobis (3-ethylbenzthiazoline sulfonic acid) (Sigma-Aldrich) diluted in 0.1 M citrate phosphate buffer, pH 4.5, containing 0.003% H2O2 as substrate. The optical density was read in an ELISA reader (Molecular Devices, Menlo Park, CA).
cDNA synthesis and RT-PCR analysis
For analysis of IL-22RA1 and IL-22RA2 mRNA expression, 106 human splenic or tonsillar B cells were cultured in medium alone or stimulated with anti-CD40 mAb (1 µg/ml) in the presence or absence of rIL-4 (10 ng/ml) for 24 h. After washing, the cells were lysed in RNA-plus (Tel-Test, Friendswood, TX), according to the manufacturers instructions, and total mRNA was extracted using chloroform, precipitated with EtOH and quantitated by optical density reading at a wavelength of 260 nm. Reverse transcription and amplification of cDNA by PCR was performed as described previously (12). PCR cycles were 30 s at 94°C, 30 s at 60°C and 30 s at 72°C for IL-22RA1 (sense: CCCCACTGGGA CACTTTCT A; anti-sense TGGCCCTTTAGGTACTGTGG), IL-22RA2 (sense: AGCTT GCCTTCTTCACTTG; anti-sense: TTGCTCTGCCTCTTATTC) and IL-10R2 (sense: AGGGT ACAATTTCAGTCCCGA; anti-sense: CGGCGTCAG CTCCA TTCTGA) (all 35 cycles) with annealing temperatures of 52 and 55°C respectively. PCR cycles were 30 s at 94°C, 30 s at 55°C and 30 s at 72°C (35 cycles) for porphobilinogen deaminase (PBGD: sense: TGAGAGTGATTCGCG TGGGTA C; antisense: CCCTGTGGTGGACATAGCAATG) (13).
Western Blot analysis
For Western blot analysis of STAT tyrosine phosphorylation, purified human splenic B cells (106 cells/ml) were stimulated with anti-CD40 mAb (1 µg/ml) and rIL-4 (20 ng/ml) or cultured in medium alone. After 48 h of incubation, cells were washed in RPMI 1640 medium and 106 cells were activated with either rIL-10 or rIL-22 (both at 10 ng/ml) for 10 min at 37°C. For control experiments, HepG2 cells were cultured in medium in the presence or absence of rIL-10 or rIL-22 (both 10 ng/ml) for 30 min. Cells were then lysed in a 1% NP-40 lysis buffer, and lysates were boiled, resolved on SDSPAGE gels and transferred electrophoretically to nitrocellulose membranes (Schleicher & Schuell, Dassel, Germany). Membranes were blocked for 1 h in TBS (150 mM NaCl and 20 mM Tris, pH 7.5), containing 5% non-fat dry milk and 0.1% Tween 20, and incubated with either polyclonal anti-phospho STAT-3 (New England Biolabs, Beverly, MA) or anti-phospho STAT-5 (Cell Signaling, Beverly, MA) antibody or an anti-Erk-2 mAb (Transduction Laboratories, Lexington, KY) for 1 h at room temperature. For some experiments, the blots were stripped and reprobed with an antibody recognizing both activated and non-activated STAT-3 proteins (Santa Cruz Biotechnology, Santa Cruz, CA). Blots were then incubated with horseradish peroxidase-conjugated goat anti-rabbit or anti-mouse antibodies (Amersham, Arlington Heights, IL) and immunoreactive proteins were visualized using the enhanced chemiluminescence assay.
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Results
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Capacity of rIL-10 and rIL-22 to modulate Ig production by B cells
IL-10 has been described to induce the production of various Ig by activated B cells. To evaluate the Ig production-inducing capacity of the IL-10 homologue IL-22, purified human splenic or tonsillar B cells were stimulated with anti-CD40 mAb in the presence of various concentrations of rIL-22 and Ig production was measured in culture supernatants by isotype-specific ELISA after 12 days of culture. As expected, stimulation of splenic B cells with anti-CD40 mAb in the presence of rIL-10 resulted in the production of IgG, IgG1, IgG3 (Fig. 1), IgA (Fig. 2) and IgD (Data not shown). Similar results were obtained when tonsillar B cells were used (Fig. 1C and data not shown), although levels of Ig production were generally lower compared to those produced by splenic B cells. However, in contrast, rIL-22, used at concentrations up to 100 ng/ml, was not able to induce the production of any of these Ig, neither in B cells isolated from spleen nor in those from tonsils (Figs 1 and 2). Binding of IL-22 to its receptor activates STAT-1, -3 and -5 (1,2). Recombinant IL-22 used in this study was functional as demonstrated by its capacity to induce activation of STAT-3 in the hepatocyte cell line HepG2 (Fig. 3) (2).

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Fig. 1. Capacity of rIL-10 and rIL-22 to induce the production of IgG, IgG1 and IgG3 by human splenic and tonsillar B cells. Purified human splenic or tonsillar B cells were stimulated with anti-CD40 mAb (1 µg/ml) in the presence of various concentrations of rIL-10 or rIL-22 in 96 well-culture plates for 12 days in IMDM supplemented with 10% FCS and culture supernatants were analyzed by isotype-specific ELISA.
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Fig. 2. Capacity of rIL-10 and rIL-22 to induce the production of IgA by human splenic and tonsillar B cells. Purified human splenic or tonsillar B cells were stimulated as indicated in the legend to Fig. 1 and culture supernatants were analyzed by IgA-specific ELISA.
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Fig. 3. rIL-22 activates STAT-3 in HepG2 cells. The hepatocyte cell line HepG2 (106 cells/ml) was cultured in medium alone (Control) or with 10 ng/ml of rIL-10 or rIL-22 for 15 min and tyrosine phosphorylation of STAT-3 was detected by Western blot analysis of whole-cell lysate. The positions of the induced STAT-3 activity (P-STAT) and constitutive STAT-3 (t-STAT) are indicated.
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To investigate the possibility that IL-22, rather than inducing Ig production by itself, might modulate Ig production induced by other cytokines, its effect on IL-4-mediated production of IgG4 and IgE was investigated. As shown in Fig. 4, rIL-22, used at 4, 20 or 100 ng/ml, did not affect the production of either isotype by splenic B cells, induced by rIL-4. In contrast, rIL-10, which by itself did not induce the production of IgE by splenic B cells, strongly synergized in a dose-dependent manner with the IL-4-induced production of IgE. Moreover, rIL-10 induced the production of IgG4, at all concentrations used, which was slightly enhanced by the addition of rIL-4.

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Fig. 4. Effect of rIL-10 and rIL-22 on rIL-4-induced production of IgG4 and IgE by human splenic B cells. Purified human splenic or tonsillar B cells were stimulated for 12 days with anti-CD40 mAb (1 µg/ml) in the absence or presence of rIL-4 (20 ng/ml) and/or various concentrations of rIL-10 and rIL-22 in 96 well-culture plates in IMDM supplemented with 10% FCS, and culture supernatants were analyzed by isotype-specific ELISA.
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Resting and activated human B cells do not express a functional IL-22RA1
At present, it is not known whether human B cells express the IL-22RA1 at their surface and therefore it cannot be excluded that the observed lack of Ig production-inducing activity of IL-22 is due to the absence of a functional IL-22R. It has been reported that activated B cells express transcripts for a soluble IL-22-binding protein, IL-22RA2, displaying 33% homology with the extracellular domain of the IL-22RA1 chain (14,15), making it plausible that these cells might express the IL-22RA1 at their cell surface as well. Using two different primer sequences that discriminate between IL-22RA1 and IL-22RA2, the expression of transcripts for each receptor chain was analyzed by RT-PCR in tonsillar and splenic B cells, stimulated with anti-CD40 mAb in the presence of rIL-4. Resting B cells did not express detectable transcripts for IL-22RA2. As expected, tonsillar (Fig. 5) or splenic (results not shown) B cells activated for 24 h expressed IL-22RA2 mRNA, confirming the results of Xu et al. (14). In contrast, however, no transcripts for the IL-22RA1 chain could be detected either in resting tonsillar B cells or in B cells activated with anti-CD40 mAb and rIL-4. In addition, the use of quantitative PCR confirmed the absence of IL-22RA1 mRNA in resting or activated splenic B cells (data not shown). Resting and activated B cells expressed transcripts for IL-10R2, whereas the HepG2 cell line, used as a positive control, expressed mRNA for both IL-10R2 and IL-22RA1.

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Fig. 5. Human tonsillar B cells, activated with anti-CD40 mAb and rIL-4, express transcripts for IL-22RA2, but not for IL-22RA1. One million purified human tonsillar B cells, either freshly isolated (NA) or stimulated for 24 h with anti-CD40 mAb (1 µg/ml) and rIL-4 (20 ng/ml) (A), were analyzed for the expression of mRNA specific for IL-22RA1, IL-22RA2 or IL-10R2. The hepatocyte cell line HepG2 served as a positive control for expression of IL-22RA1 and IL-10R2. PBGD served as a control housekeeping gene (13).
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To confirm the absence of a functional IL-22R at the cell surface of activated B cells, human splenic (Fig. 6) and tonsillar (results not shown) B cells were cultured with anti-CD40 mAb in the presence of rIL-4 for 48 h, stimulated with rIL-22 for 15 min, and phosphorylation of STAT-3 and -5 was measured by Western Blot analysis. B cells, activated under the same conditions, but stimulated with rIL-10, were used as positive control. As shown in Fig. 6, rIL-22 was not able to activate either STAT protein, in contrast to rIL-10 that activated both STAT-3 and, to a lesser extent, STAT-5. Although stimulation of resting B cells with rIL-10 also resulted in low levels of phosphorylation of STAT-3, activation of these cells with anti-CD40 mAb strongly enhanced IL-10-induced STAT-3 activation (Fig. 6), corresponding with the observed increase in IL-10R2 mRNA expression under these conditions (Fig. 5) and showing that the lack of rIL-22-mediated signal transduction was not due to suboptimal activation conditions.

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Fig. 6. rIL-22, in contrast to rIL-10, does not activate STAT-3 or -5 in human splenic B cells stimulated with anti-CD40 mAb. Purified human splenic B cells at a concentration of 106 cells/ml were stimulated with anti-CD40 mAb (1 µg/ml) and rIL-4 (20 ng/ml) (A) or cultured in medium alone (NA). After 48 h of incubation, cells were washed and 105 cells were stimulated with either rIL-10 or rIL-22 (both at 100 ng/ml) for 15 min, and tyrosine phosphorylation of STAT-3 and -5 was detected by Western blot analysis of whole-cell lysate.
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Discussion
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IL-22 is one of five recently identified IL-10 homologues of human origin (1,2) which uses a receptor consisting of a unique IL-22R (IL-22RA1) chain and the IL-10R2 chain, the latter also serving as a second chain of the IL-10R complex (1,3,4). Apart from its reported effects on the induction of acute-phase proteins by liver cells, as well as a slight inhibition of IL-4 production by Th2 cells, little is known about the functional activity of IL-22. In the present study, we show that rIL-22, in contrast to rIL-10, was not able to induce the production of IgG1 and IgG3 by purified tonsillar and splenic B cells. Moreover, rIL-22 was unable to enhance the production of IgE by B cells activated with anti-CD40 mAb and cultured in the presence of rIL-4. Although the molecular mechanisms involved in isotype switching have not been analyzed, the results presented here nevertheless exclude a role for IL-22 in the process of Ig isotype switching by human B cells.
IL-10 reportedly has differential effects on IgE and IgG4 production respectively, in that it enhances IL-4-induced expression of IgG4 transcripts and IgG4 production by peripheral blood B cells, whereas it interferes with the expression of
transcripts, thereby inhibiting the production of IgE by naive sIgD+ B cells (8). Surprisingly, although IL-4, but not IL-10, is a switch factor for IgG4 production (16), the latter cytokine was far more effective in inducing the production of this isotype by activated splenic or tonsillar B cells. Furthermore, rIL-10, which by itself was not able to induce the production of IgE, strongly synergized with rIL-4 to induce IgE production by these cells. The latter results underscore the previously described capacity of IL-10, as a result of its growth-promoting activities, to enhance the production of IgG4, as well that of IgE, by enhancing the growth and/or differentiation of B cells that are already committed to the production of either isotype (8).
As demonstrated in the present study, the reason for the absence of Ig-inducing activity is the absence of a functional IL-22R at the surface of these cells. Neither resting B cells nor B cells activated for various periods of time with anti-CD40 mAb expressed transcripts for the IL-22RA1 gene. Moreover, whereas resting, as well as activated, splenic or tonsillar B cells could be induced to activate STAT-3 and -5, following stimulation with rIL-10, no STAT-activating effects were observed with rIL-22, either in resting (results not shown) or in activated (Fig. 6) B cells, despite its capacity to activate STAT-3 in HepG2 cells. Finally, the addition of rIL-4, a cytokine with strong B cell growth- and differentiation-inducing activities, during the experimental procedures also failed to render activated B cells responsive to rIL-22. The possibility that the failure of rIL-22 to induce detectable activation of STAT proteins was due to improper or suboptimal activation conditions is to be excluded, since activation of B cells with anti-CD40 mAb strongly enhanced IL-10-induced STAT-3 and -5 activation.
The latter results were underscored by the absence of detectable IL-22RA1 mRNA in resting or activated B cells. Nevertheless, activated human B cells were found to express transcripts for a soluble binding protein of the IL-22R, IL-22RA2, confirming previously reported data in the literature (14). It was shown in the latter study that IL-22RA2 was able to inhibit IL-22-induced proliferation of a murine cell line, transfected with both the human IL-22RA1 and the CFR2-4 chain, indicating that this protein is likely to function as an IL-22 antagonist. Furthermore, based on the predominant expression of IL-22RA2 transcripts in activated B cells and monocytes, it was suggested that this soluble IL-22R is likely to play a role in inflammatory and autoimmune diseases (14). However, the physiological significance of IL-22RA2 as a natural inhibitor of IL-22-induced B cell function is not clear in view of our finding that neither resting nor activated B cells express a functional IL-22R at their cell surface. Moreover, it has to be noted that, in spite of the expression of transcripts for the IL-22RA2 gene in activated B cells, the presence of IL-22RA2 protein in the culture supernatants of these cells has yet to be demonstrated. It is possible that B cell-secreted IL-22RA2 interferes with the activity that IL-22 exerts on other cell types responsive to this cytokine, such as hepatocytes, but this hypothesis remains to be proven.
IL-22 has been shown to bind directly to the IL-10R2 chain (1), which raises the possibility that it might compete with IL-10 for binding to the common chain of the IL-10R complex, even in the absence of a functional IL-22RA1. However, under the experimental conditions used in the present study, the addition of a 50-fold molar excess of rIL-22 did not affect rIL-10-induced production of IgG1 and IgG3 by anti-CD40-activated B cells (data not shown), indicating that IL-22 does not affect, either directly or indirectly, IL-10-mediated signaling. Taken together, these results demonstrate that rIL-22, notwithstanding its structural homology to IL-10 and its use of the signaling chain of the IL-10R complex, does not have B cell-activating or differentiation-inducing effects, which is due to the absence of a functional IL-22R at the surface of these cells.
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Acknowledgements
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The authors would like to thank Dr Nathalie Lecointe, Vera Boulay and Adriana Delwayl for advice and technical assistance; Drs Austin Gurney and Francine Brière for generous gifts of cytokines and mAb; and in particular, Professor Jean-Michel Fabre, CHU St Eloi, Montpellier, for human spleen samples. S. L. is supported by MedBioMed.
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Abbreviations
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PBGDporphobilinogen deaminase
IL-TIF-
IL-10-related T cell-derived inducible factor
Rreceptor
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