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Cutting Edge: TGF-ß Inhibits Th Type 2 Development Through Inhibition of GATA-3 Expression

Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520

	Abstract

Top Abstract Introduction Materials and Methods Results and Discussion References

 
TGF-ß is an important immunomodulatory cytokine that can inhibit differentiation of effector T cells. In this report, we address the molecular mechanisms through which TGF-ß inhibits differentiation of CD4⁺ cells into Th type 2 cells. We demonstrate that TGF-ß inhibits GATA-3 expression in developing Th cells. We also show that inhibition of GATA-3 expression by TGF-ß is a major mechanism of inhibition of Th2 differentiation by TGF-ß as ectopic expression of GATA-3 in developing T cells overcomes the ability of TGF-ß to inhibit Th2 differentiation. TGF-ß likely inhibits GATA-3 expression at the transcriptional level and does so without interfering with IL-4 signaling.

	Introduction

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Regulation of the immune response toward the cellular or humoral effector pathways is an important process responsible for the defense of the organism against different types of pathogens (1). These polarized immune responses are coordinated by two types of differentiated Th cells, each secreting a signature set of cytokines required for the most effective execution of a particular response. The differentiation of these two types of Th cells is regulated by two types of cytokines that have mutually antagonistic properties on the differentiation of the opposite Th subset, thereby ensuring the predominance of a particular response.

The molecular mechanisms by which these cytokines regulate T cell differentiation have been extensively investigated. Specifically, IL-4, which is preferentially secreted by Th2 cells and is also required for their differentiation, has been shown to up-regulate expression of the transcription factor GATA-3 (2). GATA-3, which plays a crucial role in Th2 differentiation and cytokine secretion (3, 4), in turn inhibits the expression of IL-12Rß2 (2), which blocks the development of Th1 cells. In contrast, IL-12 inhibits GATA-3 expression in developing Th cells (2), thereby blocking differentiation of Th2 cells.

Another cytokine that plays a critical role in Th differentiation is TGF-ß. Addition of TGF-ß to Th1 or Th2 cultures abrogates T cell differentiation into either Th subset (5, 6), although it does not prevent the T cells from expressing activation markers (e.g., CD44^high CD45RB^low). Although TGF-ß has been shown to inhibit T cell proliferation (7), it inhibits Th differentiation even under conditions in which T cells proliferate normally (5). Although CD4⁺ T cells differentiated in the presence of TGF-ß were not capable of secreting any of the Th1 or Th2 effector cytokines, they retained their pluripotency, as demonstrated by the ability of these cells to differentiate into Th1 or Th2 type cells upon secondary culture in the absence of TGF-ß. The important role of TGF-ß in CD4⁺ T cell differentiation in vivo has also been supported recently by our studies with mice that express a dominant negative TGF-ß receptor under a T cell-specific promoter (8). T cells from these mice are insensitive to TGF-ß signaling, and a large proportion of these cells "spontaneously" differentiates in vivo into both Th1 and Th2 subsets. The molecular mechanisms by which TGF-ß prevents the differentiation of T cells presently are not known. The studies reported here were undertaken to determine the mechanism by which TGF-ß controls Th2 differentiation.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Mice

Moth cytochrome c (MCC)²-specific (AND) TCR transgenic mice were obtained from Dr. K. Bottomly, and wild-type B10.BR mice were purchased from The Jackson Laboratory (Bar Harbor, ME) and were used at 6–8 wk of age.

T cell activation and differentiation

CD4⁺ T cells from either AND TCR transgenic mice or wild-type B10.BR mice were prepared as described (8). rmIL-12 (3.5 ng/ml; Genetics Institute, Cambridge, MA) and anti-IL-4 (11B11, 10 µg/ml) were added for Th1 development; recombinant mIL-4 (1000 U/ml; Endogen, Woburn, MA) and anti-IFN- (XMG1.2, 10 µg/ml) were added for Th2 development. Recombinant huIL-2 (40 U/ml; Biogen, Cambridge, MA) was added to all stimulation conditions, and where indicated, recombinant huTGF-ß1 (3 ng/ml; R&D Systems, Minneapolis, MN) was added to the culture media.

Retroviral constructs and retroviral transduction

GFP-RV and GATA-3-RV retroviral vectors were provided by Dr. K. Murphy (Washington University, St. Louis, MO) (2). Phoenix-Eco packaging cell line (gift of Dr. G. Nolan, Stanford University, Stanford, CA) was transfected according to the protocol of Dr. Nolan. Primary T cells were activated with Ag as described, infected after 24 h using 1 ml of viral supernatant and 6 µg/ml of Lipofectamine (Life Technologies, Gaithersburg, MD), and incubated at 37°C for 24 h before being supplied with fresh media and expanded until day 5 after primary activation.

Western blot analysis

Total T cell lysates were prepared as described (8), resolved by 10% SDS-PAGE, transferred to a polyvinylidene difluoride membrane (Millipore, Bedford, MA), and probed with either anti-IL-4R, anti-IL-2R, anti-GATA-3 Abs (all obtained from Santa Cruz Biotechnology, Santa Cruz, CA), or anti-phospho(Tyr⁶⁴¹)-STAT-6 Ab (NEB, Beverly, MA), and developed using an enhanced chemiluminescence system.

FACS analyses

Staining was performed as described (8). Ten thousand events were collected, and after gating on GFP⁺ or GFP^- cells, intracellular cytokine staining was analyzed. Gates for cytokine staining were set using isotype-matched control Ab staining. Gates for GFP (FL1)-positive cells were determined using nontransduced controls.

ELISA

Cytokine levels in tissue culture supernatants were assayed by ELISA using Ab pairs for IL-5 and IL-4 (PharMingen, San Diego, CA) according to the manufacturer’s recommendations.

RNA preparation and semiquantitative RT-PCR

RNA and cDNA were prepared as described. Subsequently, each sample was subjected to PCR with sense and anti-sense primers for ß-actin and GATA-3. Primers were of the following sequences: for ß-actin, 5'-GTGGGCCGCTCTAGGCACCA (sense) and 5'-CGGTTGGCCTTAGGGTTCAGGGGGG (antisense); and for GATA-3, 5'-TCTGGAGGAGGAAACGCTAATGG (sense) and 5'-GAACTCTTCGCACACTTGGAGACTC (antisense). To specifically amplify mRNA, and not contaminating genomic DNA, primers for both ß-actin and GATA-3 were designed to span an intron. PCRs were performed at different numbers of cell cycles to ensure that comparison of PCR products for various samples is performed at the linear part of an amplification curve.

	Results and Discussion

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Several groups have previously shown that the addition of TGF-ß to CD4⁺ T cells inhibits their differentiation under Th2 culture conditions (5, 6). Importantly, this inhibition occurs even in the presence of IL-2 and is independent of the inhibitory effects of TGF-ß on T cell proliferation, thereby ruling out a role of the antiproliferative effect of TGF-ß on the inhibition of Th2 differentiation (5). To confirm this observation and to determine conditions in which TGF-ß has no effect on T cell proliferation, we stimulated AND TCR transgenic CD4⁺ cells with Ag in the presence or absence of TGF-ß1 and measured [³H]thymidine incorporation. As seen in Fig. 1A, CD4⁺ T cell proliferation was inhibited by TGF-ß at various Ag doses. Addition of 40 U/ml of exogenous IL-2 completely eliminated the inhibitory effect of TGF-ß on T cell proliferation at high doses of Ag. Therefore, we conducted all subsequent differentiation experiments under those conditions: 40 U/ml of IL-2 and 1 µg/ml of MCC peptide.

View larger version (36K): [in this window] [in a new window]   FIGURE 1. TGF-ß inhibits Th2 differentiation even under the conditions in which it does not affect CD4 T cell proliferation. A, AND T cells were stimulated with varying concentrations of MCC peptide in the presence or absence of 40 U/ml of rhIL-2 and 3 ng/ml of rhTGF-ß1. On day 3 after the start of stimulation, [3H]thymidine was added to the culture and its incorporation was measured using a ß-counter. B, CFSE-labeled AND T cells were stimulated with MCC peptide in the presence of rhIL-2 with or without TGF-ß1, and the number of cell divisions was evaluated using FACS. C and D, Primary AND T cells were stimulated and cultured under Th2 conditions in the presence or absence of rhuTGF-ß1 (3 ng/ml). On day 4 after primary activation, T cells were either restimulated with MCC peptide (1 µg/ml) in the presence of irradiated B10.BR splenic cells and cell culture supernatants were collected after 24 h and assayed for levels of IL-4 and IL-5 using ELISA (C); or cells were stimulated with PMA/ionomycin for 5 h, fixed, permeabilized, and stained with fluorescent anti-IL-5 and anti-IL-4 mAbs. Cells were analyzed by flow cytometry for IL-5 and IL-4 expression (D). Results of one representative experiment of three experiments performed are shown.

Because IL-4 signaling is crucial for Th2 differentiation, we examined how TGF-ß affects elements of the IL-4 signaling pathway. As seen in Fig. 2A, stimulation of naive T cells with anti-CD3/CD28 mAbs led to the up-regulation in expression of both chains of the IL-4 receptor (IL-4R and the common -chain). This up-regulation was not affected by addition of TGF-ß to the culture media. Therefore, inhibition of Th2 differentiation by TGF-ß does not occur through the inhibition of IL-4 receptor expression. We considered it possible that TGF-ß may interfere with signaling through the IL-4 receptor. To test this hypothesis, we examined whether TGF-ß inhibits phosphorylation of STAT-6 in response to IL-4. Preincubation of naive T cells with TGF-ß did not affect the ability of IL-4 to induce phosphorylation of STAT-6 (Fig. 2B). Therefore, the inhibition of Th2 differentiation by TGF-ß is downstream of IL-4 receptor-proximal events. Because it has been previously demonstrated that STAT-6 signaling is necessary for the induction of GATA-3, an essential factor for Th2 differentiation (3), we examined the effect of TGF-ß on GATA-3 expression. In agreement with previously reported data (2), stimulation of CD4⁺ T cells with anti-CD3 and anti-CD28 led to a significant increase in the level of GATA-3 expression in 20 h, and addition of IL-4 to the culture resulted in even higher levels of GATA-3 expression (Fig. 2C). Strikingly, addition of TGF-ß1 dramatically inhibited GATA-3 expression induced under both of these culture conditions (Fig. 2B). Results of RT-PCR analysis of the mRNA prepared from CD4⁺ T cells stimulated with or without TGF-ß revealed that TGF-ß inhibits the induction of GATA-3 expression at the mRNA level (Fig. 2D). This inhibition of GATA-3 was specific and downstream of STAT-6, because TGF-ß does not inhibit expression of IL-4R and IL-2R, and the inhibition probably does not involve IL-4 receptor proximal signaling events because TGF-ß does not inhibit STAT-6 phosphorylation. Furthermore, because under the conditions tested, TGF-ß does not affect T cell proliferation (Fig. 1), it is unlikely that TGF-ß inhibits GATA-3 expression by interfering with TCR/CD3 signaling.

View larger version (36K): [in this window] [in a new window]   FIGURE 2. TGF-ß inhibits GATA-3 expression in activated primary T cells. A and C, Magnetic bead-purified CD4+ T cells (3 x 106) were stimulated with anti-CD3/anti-CD28 mAbs (5 µg/ml each) in the presence (+) or absence (-) of rmIL-4 (1000 U/ml) and/or rhuTGF-ß1 (3 ng/ml). After 20 h of culture, total cell lysates were prepared, normalized for protein level, and resolved by 10% SDS-PAGE followed by Western immunoblotting with anti-IL-4R, anti-IL-2R (A), or anti-GATA-3 (C) specific Abs. B, To test the effect of TGF-ß on STAT-6 phosphorylation, purified CD4+ T cells were incubated with or without 3 ng/ml of rhuTGF-ß1 for 1 h followed by the addition of 1000 U/ml of rmIL-4 for another 20 min. Amounts of protein were determined by Bio-Rad protein assay to ensure equal protein loading for the analysis. D, CD4+ T cells were stimulated with anti-CD3/anti-CD28 mAbs (5 µg/ml each) in the presence (+) or absence (-) of rhuTGF-ß1 (3 ng/ml). After 20 h of culture, total cell RNA was prepared, reverse transcribed into cDNA, and amplified using ß-actin and GATA-3 specific primers. All experiments were conducted at least three times, and results of a representative experiment are shown.

To examine the effects of TGF-ß on the cytokine-producing ability of cells ectopically expressing GATA-3, we sorted GFP⁺ and GFP^- cells from different groups, restimulated them with Ag, and measured the cytokines that were secreted after 20 h of restimulation. As seen in Fig. 3, the presence of TGF-ß completely inhibited the ability of T cells differentiated under Th2 conditions to produce IL-4 and IL-5. In contrast, T cells ectopically expressing GATA-3 were markedly resistant to the inhibitory effects of TGF-ß (Fig. 3, filled columns). CD4⁺ cells transduced with GATA-3 and differentiated under Th1 conditions could also produce significant levels of IL-4 and IL-5, and this production was also resistant to inhibition by TGF-ß (Fig. 3). This TGF-ß-mediated inhibition of Th2 cytokine production is likely due to a block in differentiation of T cells into Th2 effector cells by TGF-ß rather than a block in cytokine production by the differentiated cells because TGF-ß was removed before restimulation of the differentiated T cells. Furthermore, we found that TGF-ß had no effect on IL-4 and IL-5 production by an established Th2 clone, D10 (data not shown).

View larger version (25K): [in this window] [in a new window]   FIGURE 3. Ectopic expression of GATA-3 diminishes the inhibitory effect of TGF-ß on differentiation of Th2 cytokine-secreting cells. Primary AND T cells were stimulated, infected with GFP-RV or GATA-3-RV, and cultured under Th2 conditions (top) or Th1 conditions (bottom) in the presence () or absence () of 3 ng/ml rhuTGF-ß1. Afterward, cells were harvested on day 5 after primary activation and purified by cell sorting for GFP expression, then 5 x 104 cells were restimulated with MCC peptide (1 µg/ml) in the presence of 3 x 105 irradiated B10.BR splenic cells in a total volume of 200 µl per well of 96-well flat-bottom plates. Cell culture supernatants were collected after 24 h and were assayed for levels of IL-4 (left) and IL-5 (right) using ELISA. Results of one representative experiment of three performed are shown.

View larger version (58K): [in this window] [in a new window]   FIGURE 4. Ectopic expression of GATA-3 diminishes the inhibitory effect of TGF-ß on the number of differentiating Th2 cells. Primary AND T cells were stimulated, infected with GFP-RV or GATA-3-RV, and cultured under Th1 or Th2 conditions in the presence or absence of rhuTGF-ß1 (3 ng/ml). On day 4 after primary activation, T cells were stimulated with PMA/ionomycin for 5 h. Afterward, cells were fixed, permeabilized, and stained with fluorescent anti-IL-5 and anti-IL-4 mAbs. Cells were analyzed by flow cytometry for IL-5 and IL-4 expression in either infected GFP+ or uninfected GFP- T cells. Results of one representative experiment of three performed are shown.

The ability of TGF-ß to inhibit Th differentiation through inhibition of GATA-3 expression may provide a general mechanism to redirect or switch differentiation of many different cell types. Studies using a RAG2 knockout complementation system in conjunction with embryonic stem cells with a homozygous GATA-3-null mutation (GATA-3^-/-) revealed an essential role for GATA-3 in thymocyte differentiation, as development of GATA-3-null thymocytes was blocked at the very early double negative stage (11). Recently GATA-3 has been shown to be the key regulator of CD4⁺ Th differentiation (2, 3). Timely induction and repression of GATA-3 expression seem to be critical coordinators of differentiation in different tissues. In this report we demonstrate that TGF-ß is an important regulator of GATA-3 expression in differentiating mature CD4⁺ T cells. Although we do not yet know whether TGF-ß is responsible for the regulation of GATA-3 in cells other than CD4⁺ T cells, it has been recently demonstrated that BMP (a TGF-ß family member) is required for Xenopus embryo patterning and achieves this, at least in part, through the inhibition of GATA-3 expression (12). Given the important role of TGF-ß and its other family members in embryonic development (13, 14, 15), it is conceivable that regulation of GATA-3 by TGF-ß superfamily members is an important process required at multiple stages during embryonic development and tissue differentiation.

	Acknowledgments

 
We thank Ken Murphy for a generous gift of retroviral vectors. We also thank Tom Taylor expert help in cell sorting, and Frances Manzo for help with manuscript preparation. L. Gorelik and P. E. Fields are Associates, and R.A. Flavell is an Investigator, of the Howard Hughes Medical Institute.

	Footnotes

 
¹ Address correspondence and reprint requests to Dr. Richard A. Flavell, Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06520.

² Abbreviations used in this paper: MCC, moth cytochrome c; AND MCC-specific; CFSE, 5,6-carboxyfluorescein diacetate succinimyl ester; GFP, green fluorescence protein.

Received for publication July 12, 2000. Accepted for publication August 24, 2000.

	References

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