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CUTTING EDGE |
Signaling Is Required for the In Vivo Expansion and Immunosuppressive Capacity of Regulatory CD4+CD25+ T Cells1
* I. Medizinische Klinik,
Institut für Pathologie,
Naturwissenschaftlich-Medizinisches Forschungszentrum, Johannes Gutenberg-Universität, Mainz, Germany; and
Biotechnologisch Biomedizinisches Zentrum, Universität Leipzig, Leipzig, Germany
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Abstract |
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for the in vivo function of regulatory CD4+CD25+ T cells (Treg) are controversial. A transgenic mouse model with impaired TGF- signaling specifically in T cells was used to assess the role of endogenous TGF- for the in vivo function of CD4+CD25+ Treg in a murine model of colitis induced by dextran sulfate. Transfer of wild-type, but not transgenic CD4+CD25+ Treg was found to suppress colitis in wild-type mice. In addition, by transferring CFSE-labeled CD4+CD25+ Treg we could demonstrate that endogenous TGF- promotes the expansion of CD4+CD25+ Treg in vivo. Transgenic mice themselves developed reduced numbers of peripheral CD4+CD25+ Treg and were more susceptible to the induction of colitis, which could be prevented by the transfer of wild-type Treg. These data indicate that TGF- signaling in CD4+CD25+ Treg is required for their in vivo expansion and suppressive capacity. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1 in the homeostatic regulation of the immune system was suggested by the phenotype of TGF-1–/– mice. These mice develop a rapid wasting syndrome, which leads to death at the age of 3–4 wk (1). The autoimmune phenotype of TGF-1–/– mice has been largely ascribed to the presence of activated CD4+ T cells (2). However, the precise mechanism of spontaneous T cell activation in the absence of TGF-1 remains to be elucidated. To analyze the specific effects of TGF- on T cells, we and others previously created transgenic (TG)4 mouse models with an impaired TGF- signaling pathway in T cells by overexpressing a truncated version of the TGF- type II receptor (
uTRII) under control of T cell-specific promoters (3, 4, 5). In one of these models, an autoimmune-like phenotype was observed, although these mice survived at least until 3–4 mo of age without developing overt disease (4). The TG mice generated in our group did not develop any spontaneous autoimmune disease, but showed an increased susceptibility to the induction of allergic and autoimmune diseases (3, 6, 7).
Regulatory T cells (Treg) have been defined, for the lack of a more specific marker, as small CD4+CD25+ T cells. The presence of these cells has been shown to be essential for the control of various autoreactive T cell responses (8). Ablating the generation of Treg by neonatal thymectomy on day 3 led to the development of autoimmune disease, suggesting the thymus as the site of CD4+CD25+ Treg generation (9). Recent evidence suggests that CD4+CD25+ Treg may also be induced in the periphery (10). Of note, TGF- has been implicated in the conversion of naive CD4+CD25– T cells into CD4+CD25+ T cells by the induction of Foxp3 (11, 12). However, it was reported that in TGF-1–/– mice, CD4+CD25+ Treg were able to develop up to an age of 2 wk and that autocrine TGF-1 production was not essential for these cells to exhibit suppressive activity in vivo (13). Furthermore, because of the rapid onset of inflammation in TGF-1–/– mice (1), it is difficult to study the development of Treg function over time.
Several experimental colitis models have been developed to enhance our understanding of mucosal immune regulation (14, 15). In dextran sulfate sodium (DSS)-induced colitis, mice ingest DSS for 6–10 days and develop an acute colitis that is characterized by diarrhea, gross rectal bleeding, and weight loss. Histologically, the model resembles some features of ulcerative colitis. Macrophages and neutrophils have been identified as the main effector cells of acute DSS colitis (16).
The data presented demonstrate that TGF- promotes the in vivo expansion and suppressive function of CD4+CD25+ Treg. These findings indicate that the impairment of TGF- signaling in CD4+CD25+ Treg might contribute to the increased susceptibility to autoimmune disease found in hCD2-kTRII mice.
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Materials and Methods |
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The generation and characterization of TG hCD2-kT RII mice is described elsewhere (3). All TG lines were established and maintained as heterozygotes on a FVB/N background. For colitis induction, age- and sex-matched mice between 8 and 10 wk of age were used. Age-matched nontransgenic littermates were used as controls. Animal care was in accordance with the governmental and institutional guidelines.
Induction of DSS colitis
DSS (ICN Biochemicals, Cleveland, OH) with a molecular weight of 36–40 kDa was dissolved in deionized autoclaved water to provide a working solution of 2.25 or 3% (w/v). Mice were given free access to water substituted with DSS for 9 days.
Collection of colonic tissue
A 0.75-cm segment from the distal colon was removed and embedded in paraffin. Five-micrometer sections were stained with H&E.
Histological and endoscopic scoring
Histological scoring was performed by a pathologist in a blinded fashion as described before (17). The experimental setup for endoscopic scoring consisted of a miniendoscope, a light source, and an air pump to inflate the mouse colon. Scoring was performed in a blinded fashion, giving 0–3 points for vascularity, translucency, and stool.
Lymphocyte separation and adoptive cell transfer
CD25+ lymphocytes from spleens of 7- to 9-wk-old mice were separated with MACS beads. In a second step, CD4+CD25+ cells were sorted with a FACSVantage cell sorter (BD Biosciences, Heidelberg, Germany). Purity of cell separation ranged around 95% as assessed by flow cytometry. For some experiments, 7.5 x 105 CD4+CD25+ or CD4+CD25– T cells were injected i.p. 8 h before colitis induction. For CFSE labeling, cells were incubated in 2 µM CFSE (Molecular Probes, Leiden, The Netherlands) in PBS at 37°C for 10 min. Isolation of lamina propria mononuclear (LPMN) cells was performed essentially as described previously (14).
Flow cytometry
For flow cytometric analysis, cells were stained with CD25-PE (Miltenyi Biotec, Auburn, CA) and CD4-PE-Cy7 (Caltag Laboratories, Burlingame, CA). Flow cytometry was performed with a FACSCalibur using CellQuest software (BD Biosciences). At least 1 x 106 cells were analyzed.
Cell culture and cell proliferation assays
Cell culture was performed essentially as described elsewhere (3). Supernatants were collected after 60 h and frozen in liquid nitrogen. Suppressor assays were performed essentially as described previously (18).
Cytokine assays
Concentrations of IFN-
, IL-5, IL-6, IL-10 (Mouse BD OptEIA ELISA Sets; BD Pharmingen, San Diego, CA), and TNF-
(R&D Systems, Minneapolis, MN) in cell culture supernatants were measured according to the manufacturer’s instructions.
Statistical analysis
Mean ± SEM are given. For the comparison of groups, the two-sided Wilcoxon rank sum test was applied and a p < 0.05 was considered to be significant. Experiments were repeated at least twice with similar results.
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Results |
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signaling for their in vivo suppressive capacity
TGF- has been suggested as an effector cytokine of CD4+CD25+ Treg function (19, 20, 21). However, the effects of TGF- on CD4+CD25+ Treg themselves are largely unknown. Therefore, the suppressive capacity of CD4+CD25+ Treg isolated from wild-type (WT) and from hCD2-kTRII TG mice was compared in a transfer model. CD4+CD25+ or CD4+CD25– T cells isolated from spleens of WT or hCD2-kTRII mice were transferred into WT mice before colitis induction with 3% DSS. WT CD4+CD25+ Treg mediated a significant protection from colitis, which was characterized by a reduced weight loss and a lower endoscopic and histological colitis score (Fig. 1, A–D). In contrast, CD4+CD25+ Treg isolated from hCD2-kTRII mice lacked a protective effect (Fig. 1, A–D). No in vivo suppressive capacity was observed for CD4+CD25– T cells isolated either from WT or TG mice (percentage of initial weight: WT CD4+CD25–, 85 ± 3.3; TG CD4+CD25–, 85 ± 2.3; WT PBS, 82 ± 1.4; histological colitis score WT CD4+CD25–, 5 ± 0; TG CD4+CD25–, 5 ± 0; WT PBS, 5 ± 0.1; mean ± SEM from at least four animals). Of note, the in vitro suppressive capacity of TG CD4+CD25+ Treg was not decreased as compared with WT CD4+CD25+ Treg (Fig. 1E), underlining that the in vitro suppressor assays do not adequately reflect the in vivo situation.
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promotes the expansion of CD4+CD25+ Treg in vivo
To analyze whether the reduced suppressive capacity of TG CD4+CD25+ Treg was attributable to a defective in vivo migration or proliferation, WT and TG CD4+CD25+ Treg were labeled with CFSE before transfer into WT mice and colitis induction. On day 2 of colitis, CD4+CD25+CFSE+ cells could be found in mesenteric lymph nodes (MLN) and to a lesser extent in the spleen, but not in the blood (data not shown). There was no difference between WT and TG CD4+CD25+CFSE+ cell numbers in MLN and spleen at this time point, arguing against a defect in migration induced by the impairment of TGF- signaling (CD4+CD25+CFSE+ cells of total MLN cells: TG, 0.013% vs WT, 0.012%). On day 2 of colitis, most CD4+CD25+CFSE+ cells were undivided, but on day 4, only 40–50% of WT, but 80–90% of TG CD4+CD25+CFSE+ cells remained undivided (Fig. 2, A and C). The CFSE+ cells were confirmed to be CD4+ and CD25+ by flow cytometry (Fig. 2B). Upon transfer of CFSE+CD4+CD25+ cells into healthy WT mice or immunodeficient SCID mice, no difference in proliferation was observed between TG and WT CD4+CD25+ Treg until day 4 after transfer (Fig. 2D). In vitro, TGF- alone or in combination with IL-2 was not sufficient to induce proliferation of CD4+CD25+ T cells (Fig. 2E and data not shown). These results demonstrate that endogenous TGF- significantly contributes to the expansion of CD4+CD25+ Treg in vivo, but indicates the involvement of other mediators of inflammation yet to be identified.
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kTRII mice develop decreased numbers of peripheral CD4+CD25+ Treg
Since the expansion of CD4+CD25+ Treg was reduced upon transfer and colitis induction, we aimed to analyze CD4+CD25+ Treg numbers in hCD2-kTRII TG mice. No difference was observed in thymic CD4+CD8–CD25+ T cell numbers between TG and WT mice of various ages (Fig. 3A). In peripheral lymphoid organs of BALB/c mice, the numbers of CD4+CD25+ Treg seem to be maintained from an age of 2 wk onward (22). Accordingly, in FVB/N WT mice between 3 and 7 wk of age, the numbers of peripheral CD4+CD25+ Treg were relatively stable (Fig. 3B). However, in TG mice the numbers of CD4+CD25+ Treg decreased between the age of 4–6 wk, but remained stable thereafter (Fig. 3B).
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kTRII mice and can be completely reversed by the transfer of WT CD4+CD25+ Treg
To support a role for endogenous TGF- for the functional development of CD4+CD25+ Treg in vivo, an acute colitis was induced in hCD2-kTRII mice by feeding 2.25% DSS in drinking water over a period of 9 days. TG mice developed a severe colitis, whereas WT mice developed only a mild colitis at this concentration of DSS (Fig. 4, A–C). Furthermore, mononuclear cells isolated from the lamina propria of TG coli showed an increased cytokine production, mainly of IL-6, IL-10, and IFN- as compared with WT (Fig. 4D).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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for the in vivo function of CD4+CD25+ Treg are controversial. Whereas it was reported that CD4+CD25+ Treg isolated from TGF-1–/– mice do not protect recipient mice from colitis in the SCID transfer colitis model (20) and that the suppression of islet-specific CD8+ T cells by CD4+CD25+ Treg is mediated by TGF- (21), it was also reported that TGF-1 expression is not essential for the in vivo function of CD4+CD25+ Treg (13). In the colitis model described, TGF- signaling in effector T cells was not essential for suppression mediated by CD4+CD25+ Treg. However, significant differences exist in the TG mice, disease models, and the population of effector cells analyzed. In other experiments, the suppression of inflammation mediated by CD4+CD25+ Treg could be abrogated by injecting neutralizing TGF- Ab (23, 24, 25, 26).
However, from the experiments using TGF1–/– mice or anti-TGF- treatment, it remains unclear whether TGF- is required as an effector cytokine or whether CD4+CD25+ Treg themselves require TGF- for their proper in vivo suppressive function. We therefore investigated the role of TGF- signaling for the function of CD4+CD25+ Treg. The decreased in vivo suppressive capacity of TG CD4+CD25+ Treg demonstrates that the effect of endogenous TGF- on CD4+CD25+ Treg themselves is essential for their proper in vivo suppressive capacity. It has previously been demonstrated that the expression of Foxp3, a transcription factor essential for the development and function of CD4+CD25+ Treg, is modulated by TGF- in vitro (11, 12) and in vivo (18). Therefore, Foxp3 might mediate some of the effects induced by TGF-.
It was recently reported that TGF-1–/– mice have normal numbers of CD4+CD25+ Treg after birth, indicating that CD4+CD25+ Treg are able to develop in complete absence of endogenous TGF-1 expression (13, 27). However, there is increasing evidence that TGF- might regulate the peripheral pool of CD4+CD25+ Treg. In vitro experiments with human naive T cells suggested that TGF- may expand precommitted CD4+CD25+ Treg (28). In vivo, it was shown that a transient pulse of TGF- in the islets during the priming phase of diabetes protected mice from disease and increased the number of intraislet CD4+CD25+ T cells (29). TGF- was shown to convert naive CD4+CD25– responder T cells to CD4+CD25+ T cells in the presence of TCR stimulation (11, 12). We here describe a reduction in the numbers of peripheral CD4+CD25+ Treg in mice with impaired TGF- signaling in T cells after the age of 4 wk. This could either be due to a defect in the conversion of CD4+CD25– T cells to CD4+CD25+ Treg or to a decreased expansion of preformed CD4+CD25+ Treg in vivo. We therefore analyzed the proliferative capacity of CD4+CD25+ Treg with impaired TGF- signaling in a transfer model and could demonstrate that endogenous TGF- promotes the in vivo expansion of CD4+CD25+ Treg in the setting of inflammation. No difference in the proliferative capacity of TG and WT Treg was observed in vitro or in vivo upon transfer into immunocompetent healthy and immunodeficient SCID mice. This indicates that TGF- signaling alone is not sufficient to induce proliferation in Treg and that in vivo factors induced by inflammation might cooperate with TGF- to induce proliferation.
In conclusion, we demonstrate here for the first time, that the effect of endogenous TGF- on Treg themselves is required for their proper in vivo expansion and in vivo suppressive capacity.
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Acknowledgments |
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Footnotes |
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1 This work was supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 548. 
2 S.H. and C.S. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Christoph Schramm, I. Medical Department, Johannes Gutenberg-Universität, Langenbeckstrasse 1, 55101 Mainz, Germany.
4 Abbreviations used in this paper: TG, transgenic; Treg, regulatory T cell; DSS, dextran sulfate sodium; LPMN, lamina propria mononuclear; MLN, mesenteric lymph node; WT, wild type.
Received for publication June 15, 2004. Accepted for publication September 23, 2004.
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Y. Carrier, J. Yuan, V. K. Kuchroo, and H. L. Weiner Th3 Cells in Peripheral Tolerance. II. TGF-beta-Transgenic Th3 Cells Rescue IL-2-Deficient Mice from Autoimmunity J. Immunol., January 1, 2007; 178(1): 172 - 178. [Abstract] [Full Text] [PDF]
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J. Nilsson, A. Boasso, P. A. Velilla, R. Zhang, M. Vaccari, G. Franchini, G. M. Shearer, J. Andersson, and C. Chougnet HIV-1-driven regulatory T-cell accumulation in lymphoid tissues is associated with disease progression in HIV/AIDS Blood, December 1, 2006; 108(12): 3808 - 3817. [Abstract] [Full Text] [PDF]
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J. J. Kobie, P. R. Shah, L. Yang, J. A. Rebhahn, D. J. Fowell, and T. R. Mosmann T Regulatory and Primed Uncommitted CD4 T Cells Express CD73, Which Suppresses Effector CD4 T Cells by Converting 5'-Adenosine Monophosphate to Adenosine J. Immunol., November 15, 2006; 177(10): 6780 - 6786. [Abstract] [Full Text] [PDF]
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C. Becker, H. Dornhoff, C. Neufert, M. C. Fantini, S. Wirtz, S. Huebner, A. Nikolaev, H.-A. Lehr, A. J. Murphy, D. M. Valenzuela, et al. Cutting Edge: IL-23 Cross-Regulates IL-12 Production in T Cell-Dependent Experimental Colitis. J. Immunol., September 1, 2006; 177(5): 2760 - 2764. [Abstract] [Full Text] [PDF]
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C. Cassan, E. Piaggio, J. P. Zappulla, L. T. Mars, N. Couturier, F. Bucciarelli, S. Desbois, J. Bauer, D. Gonzalez-Dunia, and R. S. Liblau Pertussis Toxin Reduces the Number of Splenic Foxp3+ Regulatory T Cells J. Immunol., August 1, 2006; 177(3): 1552 - 1560. [Abstract] [Full Text] [PDF]
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 K. Wing, Z. Fehervari, and S. Sakaguchi Emerging possibilities in the development and function of regulatory T cells Int. Immunol., July 1, 2006; 18(7): 991 - 1000. [Abstract] [Full Text] [PDF]
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M C Fantini, C Becker, I Tubbe, A Nikolaev, H A Lehr, P Galle, and M F Neurath Transforming growth factor {beta} induced FoxP3+ regulatory T cells suppress Th1 mediated experimental colitis Gut, May 1, 2006; 55(5): 671 - 680. [Abstract] [Full Text] [PDF]
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M. Ono, J. Shimizu, Y. Miyachi, and S. Sakaguchi Control of Autoimmune Myocarditis and Multiorgan Inflammation by Glucocorticoid-Induced TNF Receptor Family-Related Proteinhigh, Foxp3-Expressing CD25+ and CD25- Regulatory T Cells. J. Immunol., April 15, 2006; 176(8): 4748 - 4756. [Abstract] [Full Text] [PDF]
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J. Harnaha, J. Machen, M. Wright, R. Lakomy, A. Styche, M. Trucco, S. Makaroun, and N. Giannoukakis Interleukin-7 Is a Survival Factor for CD4+ CD25+ T-Cells and Is Expressed by Diabetes-Suppressive Dendritic Cells Diabetes, January 1, 2006; 55(1): 158 - 170. [Abstract] [Full Text] [PDF]
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R. H. Prabhala, P. Neri, J. E. Bae, P. Tassone, M. A. Shammas, C. K. Allam, J. F. Daley, D. Chauhan, E. Blanchard, H. S. Thatte, et al. Dysfunctional T regulatory cells in multiple myeloma Blood, January 1, 2006; 107(1): 301 - 304. [Abstract] [Full Text] [PDF]
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M. Delgado, A. Chorny, E. Gonzalez-Rey, and D. Ganea Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo J. Leukoc. Biol., December 1, 2005; 78(6): 1327 - 1338. [Abstract] [Full Text] [PDF]
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 A. J. M. van Oosterhout and N. Bloksma Regulatory T-lymphocytes in asthma Eur. Respir. J., November 1, 2005; 26(5): 918 - 932. [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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F. Ghiringhelli, P. E. Puig, S. Roux, A. Parcellier, E. Schmitt, E. Solary, G. Kroemer, F. Martin, B. Chauffert, and L. Zitvogel Tumor cells convert immature myeloid dendritic cells into TGF-{beta}-secreting cells inducing CD4+CD25+ regulatory T cell proliferation J. Exp. Med., October 3, 2005; 202(7): 919 - 929. [Abstract] [Full Text] [PDF]
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X. Huang, J. Zhu, and Y. Yang Protection against Autoimmunity in Nonlymphopenic Hosts by CD4+CD25+ Regulatory T Cells Is Antigen-Specific and Requires IL-10 and TGF-{beta} J. Immunol., October 1, 2005; 175(7): 4283 - 4291. [Abstract] [Full Text] [PDF]
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T. Banovic, K. P. A. MacDonald, E. S. Morris, V. Rowe, R. Kuns, A. Don, J. Kelly, S. Ledbetter, A. D. Clouston, and G. R. Hill TGF-{beta} in allogeneic stem cell transplantation: friend or foe? Blood, September 15, 2005; 106(6): 2206 - 2214. [Abstract] [Full Text] [PDF]
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S. J. McMillan, G. Xanthou, and C. M. Lloyd Manipulation of Allergen-Induced Airway Remodeling by Treatment with Anti-TGF-{beta} Antibody: Effect on the Smad Signaling Pathway J. Immunol., May 1, 2005; 174(9): 5774 - 5780. [Abstract] [Full Text] [PDF]
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 X. L. Zhang, N. Topley, T. Ito, and A. Phillips Interleukin-6 Regulation of Transforming Growth Factor (TGF)-{beta} Receptor Compartmentalization and Turnover Enhances TGF-{beta}1 Signaling J. Biol. Chem., April 1, 2005; 280(13): 12239 - 12245. [Abstract] [Full Text] [PDF]
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