| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
CUTTING EDGE |
*
Department of Molecular and Developmental Biology, The Institute of Medical Science, University of Tokyo, Tokyo, Japan;
Core Research for Evolutionary Science and Technology, Saitama, Japan; and
Department of Immunology, DNAX Research Institute, Palo Alto, CA 94304
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
The promoter regions of IL-4 and IL-5 have been analyzed extensively and various transcription factors required for the activation of these genes have been identified (2, 3, 5, 6). However, it has now become clear that the expression level mediated by the IL-4 promoter alone is extremely weak, suggesting that optimal IL-4 gene transcription may require a distinct regulatory region outside of the promoter (7). Although most studies on the control of cytokine gene expression have focused on the proximal promoter regions, many tissue- and developmental stage-specific genes are regulated at the level of chromatin structure. Active genes are often found in regions of "decondensed" chromatin associated with acetylated histones, and are hypomethylated (8). We previously identified three DNase I hypersensitive (DH)4 sites, HSS1, HSS2, and HSS3, within the mouse IL-13/IL-4 intergenic region (9). Intriguingly, HSS1 and HSS2 are induced during Th2 development (9). Moreover, it has recently been demonstrated that the DNA segment containing HSS1 and HSS2, termed conserved noncoding sequence (CNS)-1, is highly conserved among mammals and the 1.3-kb genomic region containing CNS-1 is crucial for the expression of IL-4, IL-13, and IL-5 (10). Agarwal et al. (11, 12) also identified several Th2-specific as well as non-Th subset-specific DH sites in the flanking regions of the IL-4 and IL-13 genes.
The critical role of Stat6 in Th2 development has been shown in gene-disrupted mice (13, 14, 15). Conditional activation of Stat6 by using a Stat6-estrogen receptor (ER) fusion protein (Stat6:ER) proved that the activation of Stat6 in addition to a TCR signal is sufficient to induce Th2 differentiation (16). It has been demonstrated that Stat6 is required to induce DH sites in the flanking regions of the IL-13 and IL-4 genes (11). However, it remained to be determined whether the activation of Stat6 alone is sufficient to create an open chromatin conformation, especially at the IL-4/IL-13 intergenic region.
GATA-3 is selectively expressed in Th2 subset, and plays a crucial role in Th2 development (17, 18, 19). However, the mechanism by which GATA-3 regulates IL-4 and IL-13 gene expression remains to be clarified. Several studies have provided evidence that GATA-3 directly activates the IL-5 promoter (17, 20, 21, 22), but not the IL-4 promoter (21, 22, 23), suggesting that GATA-3 controls IL-4 expression through the regulatory region outside of the promoter or by a mechanism other than transactivation, such as chromatin remodeling. We have recently demonstrated that ectopic expression of GATA-3 results in the induction of Th2-specific DH site within the second intron of the IL-4 gene in a fully differentiated Th1 clone (23). Ouyang et al. (24) recently showed that, in developing Th2 cells, overexpression of GATA-3 leads to the induction of Th2-specific DH sites in the flanking region of the IL-4 gene even in a Stat6-deficient background. However, the role for GATA-3 in the chromatin remodeling at the flanking region of the IL-13 gene has not been addressed. Moreover, as for the IL-4/IL-13 intergenic region, the molecular mechanism underlying Th2-specific chromatin remodeling remains unknown. It would be important to determine whether a single factor is responsible for the induction of an extended open chromatin conformation over the entire IL-4/IL-13 locus.
In this study, we demonstrate that the ectopic activation of either Stat6 or GATA-3 during Th cell differentiation induces chromatin remodeling not only at the flanking regions of the IL-4 and IL-13 genes but also at the IL-4/IL-13 intergenic region, which directly overlaps with the coordinate regulatory region for the clustered Th2-specific cytokine genes. We also show, for the first time, that GATA-3 associates with HSS2-spanning region specifically in Th2 cells. Furthermore, we identified Th2-specific protein complex that interacts with HSS1 in T cell activation-dependent manner.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
Recombinant mouse IL-2, IL-4, IL-12, and purified rat anti-mouse IL-4 Ab (11B11) were purchased from R&D Systems (Minneapolis, MN).
Retroviral transduction
Purification by cell sorting and primary stimulation of naive Th
cells from DO11.10
TCR
ß-transgenic mice
(25) was performed as previously described
(9). Retroviral constructs pMX-ER, pMX-Stat6:ER, and
pMXI-GATA-3-EGFP and the protocol for preparation of retrovirus were
described previously (16, 19, 23). On days 1 and 2 after
primary antigenic stimulation under Th1-polarizing conditions, cells
were infected with retrovirus-containing supernatants in the presence
of 0.5 µg/ml polybrene (Sigma, St. Louis, MO). Cells infected with
Stat6:ER- or ER-encoding retrovirus were thereafter cultured in the
presence of 1 µM 4-hydroxytamoxifen (4-HT; Research Biochemicals,
Natick, MA). On day 7, cells were sorted on the basis of enhanced green
fluorescent protein (EGFP) expression. Cells were allowed to develop
with weekly antigenic stimulation for another 2 consecutive weeks.
DNase I hypersensitivity analysis
Nuclei were isolated from cells (2 x 107) stimulated with PMA and A23187 as previously described (9). Varying amounts of DNase I (Worthington Biochemical, Lakewood, NJ) were added to aliquots of nuclei (1 x 108/ml), which were then incubated at 37°C for 12.5 min. Purification of genomic DNA, Southern blotting, and hybridization were conducted as described (9).
EMSA
Nuclear extracts were prepared from unstimulated or stimulated
in vitro-differentiated Th1 and Th2 cells, as previously described
(20). The sequence of the synthetic oligonucleotides used
as probes are given in Fig. 2
a. In the competition
experiments, the following oligonucleotides were used (only the sense
strands are shown): AP-1 5'-CGCTTGATGACTCAGCCGGAA-3';
TGATA 5'-GTTAGAGATAGCATCGCCCCA-3'.
|
|
Results and Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
We examined the functional contribution of Stat6 in the
Th2-specific remodeling of the IL-4/IL-13 intergenic region. Although
Stat6 is expressed in both Th1 and Th2 cells, its phosphorylation
and activation occur exclusively in Th2 cells (26).
Thus, we used Stat6:ER, a fusion protein of Stat6 and the modified
hormone-binding domain of the ER (16). It is activated by
estrogen analogues such as 4-HT, allowing us to analyze the
Stat6-specific effects independently of IL-4 stimulation (16, 27). We introduced retroviral vectors encoding Stat6:ER
bicistronically with EGFP (pMX-Stat6:ER) or the control ER construct
(pMX-ER) into naive Th cells of DO11.10
TCRß-transgenic mice
and let them develop under Th1-polarizing conditions in the presence of
4-HT. On day 7, EGFP+ cells were purified by cell
sorting and allowed to develop with weekly antigenic stimulation for
another 2 consecutive weeks, after which the chromatin structure of the
IL-4/IL-13 locus was analyzed. As shown previously (16),
introduction of pMX-Stat6:ER, but not pMX-ER, resulted in the induction
of IL-4 production as well as a reduction in IFN-
production (data
not shown).
In RV-Stat6:ER-infected cells, Th2-specific DH sites HSS1 and HSS2
(9) were induced in the IL-4/IL-13 intergenic region (Fig. 1a). In these cells, all the
previously identified Th2-specific DH sites in the flanking regions of
the IL-13 and IL-4 genes (11) were observed as well (Fig. 1a). Additionally, two novel DH sites, both of which we
designated II', were identified within the second and first intron of
the IL-4 and IL-13 genes, respectively (Fig. 1a). The same
DH sites were also detected in a Th2 clone (D10), but not in a Th1
clone (HDK1) or in in vitro-differentiated Th1 cells (data not shown).
In contrast, none of the Th2-specific DH sites were observed in
RV-ER-infected cells; only those that have been shown to exist in both
Th subsets were observed (Fig. 1a). These results indicate
that the activation of Stat6 during Th cell differentiation is
sufficient for the induction of an accessible chromatin configuration
at the IL-4/IL-13 intergenic region as well as at the flanking regions
of the IL-4 and IL-13 genes.
|
ß-transgenic mice
with a GATA-3-encoding retrovirus (R-GATA-3-EGFP) and let them develop
under Th1-polarizing conditions. An open chromatin conformation was
induced in the IL-4/IL-13 intergenic region, as evidenced by the
appearance of the Th2-specific DH sites, HSS1 and HSS2 (Fig. 1
b). Th2-specific DH sites were also induced in the flanking
regions of the IL-4 and IL-13 genes (Fig. 1b). Taken
together, we propose that the induction of Th2-specific chromatin
remodeling of the entire IL-4/IL-13 locus is mediated through GATA-3,
which functions downstream of Stat6. We cannot rule out the possibility
that the three sets of DH sites, one in the IL-4 locus, another in the
IL-4/IL-13 intergenic region, and third in the IL-13 locus, are
independently regulated and are induced in distinct subpopulations of
cells. Although currently no reliable experimental technique is
available to analyze DH sites at a single-cell level, it would be
important to address this issue in future by clonal or single cell
studies. Th2-specific factors interact with the region spanning HSS1 and HSS2
It recently has been demonstrated that the DNA segment containing HSS1 and HSS2, termed CNS-1, is highly conserved among mammals and the 1.3-kb genomic region containing CNS-1 is crucial for the expression of the IL-4, IL-13, and IL-5 genes (10). Detection and analysis of molecules that associate with HSS1 and HSS2 should facilitate further elucidation of the molecular events occurring in Th2-specific, coordinate expression of these Th2 cytokine genes.
Inspection of CNS-1 by the aid of a computer data base
(MatInspector V2.2;
http://transfac.gbf-braunschweig.de/cgi-bin/matSearch/matsearch.pl)
identified several transcription factor binding motifs including those
for NFAT, c-Myb, AP-1, activating transcription factor, cAMP response
element binding protein, and Ikaros (Fig. 2a, GenBank
accession numbers AC005742: 99820–100225). Interestingly, a potential
binding site for GATA-3 was identified at the 5' end of CNS-1, which
perfectly overlaps with the HSS2 (Figs. 1c and
2a). Although several GATA-3 binding sites have been
reported in the IL-4/IL-13 locus (12, 22), binding of
GATA-3 to CNS-1 has not been addressed. Thus, we performed EMSA using
in vitro-differentiated DO11.10 Th1 and Th2 nuclear extracts. Using
oligonucleotide probe IIa, a DNA-protein complex that we
designated HSS2-I was formed with Th2 but not with Th1 nuclear extracts
(Fig. 2, a and b). Intensity of the band
containing HSS2-I increased after T cell activation (Fig. 2b). The formation of HSS2-I was abrogated by introducing a
substitution mutation into WGATAR motif (data not shown), or by adding
excess amounts of an oligonucleotide containing a GATA-3 binding site
from the human TCR gene enhancer
(TGATA) (Fig. 2b). Conversely,
IIa, but not the mutated IIa oligonucleotide
inhibited the binding of GATA-3 to the TGATA
oligonucleotide (Fig. 2b). Moreover, pretreatment with
anti-GATA-3 Ab supershifted HSS2-I (Fig. 2b). These
results indicate that HSS2-I contains GATA-3.
As for HSS1-spanning region, potential binding sites for known
Th2-specific transcription factors such as Stat6, GATA-3, or c-Maf were
not detected (Fig. 2a). To investigate the NFs interacting
with HSS1, we performed EMSA using sets of overlapping oligonucleotide
probes spanning HSS1 (Fig. 2a, Ia-Ig).
Several constitutive as well as inducible complexes were identified
using Th1 and Th2 nuclear extracts (Fig. 2c). Interestingly,
when oligonucleotides If and Ig were used as
probes, T cell activation-inducible complexes were detected
specifically in Th2 nuclear extracts (Fig. 2c). Cross
competition assays with either oligonucleotide revealed that the
binding proteins recognize the same DNA sequence within these
overlapping probes (Fig. 2d). We designated these
complexes HSS1-I. The inducibility of HSS1-I correlates with the
enhanced accessibility of HSS1 upon T cell activation (9).
The overlapping portion of probes If and Ig
contained the DNA sequence closely resembling the consensus AP-1
binding site (Fig. 2a). The formation of HSS1-I was
efficiently inhibited by adding excess amounts of an oligonucleotide
containing the consensus AP-1 binding site, but not by the
Ig oligonucleotide with a substitution mutation in the
putative AP-1 binding motif (Fig. 2d). These results suggest
that HSS1-I may include DNA binding proteins identical or closely
related to AP-1. The Fos/Jun heterodimer has been shown to disrupt the
nucleosome structure and to facilitate the binding of a second
transcription factor in vitro (28), suggesting the
potential involvement of HSS1-I in alteration of the chromatin
structure. Because each component of the AP-1 family proteins has been
detected in both Th1 and Th2 nuclear extracts (29), HSS1-I
may contain additional Th2-specific NF(s). It has been demonstrated
that c-Maf can activate the IL-4 promoter synergistically with Jun B
(30). However, the nucleotide sequence surrounding the
putative AP-1 site in the probe does not match the consensus binding
site for c-Maf (Fig. 2a) and anti-c-Maf Ab failed to
supershift HSS1-I (data not shown).
Recently, it has been shown that following T cell activation, a
Th2-specific, cyclosporin A-sensitive DH site designated
VA is induced at 3' of the IL-4 gene
(12). Interestingly, canonical GATA sites reside in the
region surrounding VA, and GATA-3 binds in vivo
to the genomic region spanning VA
(12). As for the IL-4/IL-13 intergenic regulatory region,
our results indicate possible binding of GATA-3 to the DNA segment
encompassing Th2-specific DH site, HSS2 (Fig. 2b). It would
thus appear that GATA-3 induces chromatin remodeling through direct
association with Th2-specific DH sites scattered over the entire
IL-4/IL-13 locus. Consistent with this notion, GATA-1, another member
of the GATA family of proteins, has been shown to play an essential
role in the induction of the erythroid-specific DH site of the human
ß-globin locus control region and in the chicken
ßA/
-globin gene through direct association
with its recognition sites (31, 32). We have recently
shown that a GATA-3 mutant lacking its N-terminal finger, and thus
unable to bind to its recognition sequence, is still capable of
redirecting the Th1-differentiated phenotype of a Th1 clone into IL-4
expressing cells (23). Therefore, GATA-3 might regulate
the chromatin structure of the IL-4/IL-13 locus in the absence of
direct DNA binding as well, presumably through recruiting chromatin
remodeling complexes. It is also possible that GATA-3 up-regulates
Th2-specific cytokine transcription from the "opened" HSS2 in fully
differentiated effector Th2 cells. In either case, it would be
important to determine whether GATA-3 interacts with the chromatin of
the HSS2 region in vivo.
In conclusion, our results revealed that GATA-3 induces the chromatin remodeling at the IL-4/IL-13 intergenic regulatory region, and Th2-specific protein complexes containing GATA-3 associate with this region. Based on these findings, we propose that establishment of an accessible chromatin conformation at the IL-4/IL-13 intergenic regulatory region by GATA-3 may underlie the coordinate expression of the clustered Th2-specific cytokine genes.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Current address: Howard Hughes Medical Institute, University of Chicago, 5841 South Maryland Avenue, MC1028, Chicago, IL 60637.
3 Address correspondence and reprint requests to Dr. Shoichiro Miyatake, Department of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
4 Abbreviations used in this paper: DH, DNase I hypersensitive; CNS, conserved noncoding sequence; EGFP, enhanced green fluorescent protein; ER, estrogen receptor; 4-HT, 4-hydroxytamoxifen
Received for publication September 13, 2000. Accepted for publication October 16, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
production from developing Th1 cells in addition to inducing IL-4 and IL-5 levels. Clin. Immunol. 91:134.[Medline]
This article has been cited by other articles:
|
|
 |
|
  E. J. Scheinman and O. Avni Transcriptional Regulation of Gata3 in T Helper Cells by the Integrated Activities of Transcription Factors Downstream of the Interleukin-4 Receptor and T Cell Receptor J. Biol. Chem., January 30, 2009; 284(5): 3037 - 3048. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Ribeiro de Almeida, H. Heath, S. Krpic, G. M. Dingjan, J. P. van Hamburg, I. Bergen, S. van de Nobelen, F. Sleutels, F. Grosveld, N. Galjart, et al. Critical Role for the Transcription Regulator CCCTC-Binding Factor in the Control of Th2 Cytokine Expression J. Immunol., January 15, 2009; 182(2): 999 - 1010. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Wurster and M. J. Pazin BRG1-Mediated Chromatin Remodeling Regulates Differentiation and Gene Expression of T Helper Cells Mol. Cell. Biol., December 15, 2008; 28(24): 7274 - 7285. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhang, S. Saccani, H. Shin, and B. S. Nikolajczyk Dynamic Protein Associations Define Two Phases of IL-1{beta} Transcriptional Activation J. Immunol., July 1, 2008; 181(1): 503 - 512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Zhao, B. Zheng, Y. Huang, D. Yang, S. Katzman, C. Chang, D. Fowell, and W.-p. Zeng Interaction between GATA-3 and the Transcriptional Coregulator Pias1 Is Important for the Regulation of Th2 Immune Responses J. Immunol., December 15, 2007; 179(12): 8297 - 8304. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. T. Kim, P. E. Fields, and R. A. Flavell Demethylation of a specific hypersensitive site in the Th2 locus control region PNAS, October 23, 2007; 104(43): 17052 - 17057. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rose, M. Lichtenheld, M. R. Foote, and B. Adkins Murine Neonatal CD4+ Cells Are Poised for Rapid Th2 Effector-Like Function J. Immunol., March 1, 2007; 178(5): 2667 - 2678. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Strempel and D. Vercelli Functional Dissection Identifies a Conserved Noncoding Sequence-1 Core That Mediates IL13 and IL4 Transcriptional Enhancement J. Biol. Chem., February 9, 2007; 282(6): 3738 - 3746. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. B. Webster, Y. Rodriguez, W. T. Klimecki, and D. Vercelli The Human IL-13 Locus in Neonatal CD4+ T Cells Is Refractory to the Acquisition of a Repressive Chromatin Architecture J. Biol. Chem., January 5, 2007; 282(1): 700 - 709. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. V. Prasanth and D. L. Spector Eukaryotic regulatory RNAs: an answer to the 'genome complexity' conundrum Genes & Dev., January 1, 2007; 21(1): 11 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Shinnakasu, M. Yamashita, K. Shinoda, Y. Endo, H. Hosokawa, A. Hasegawa, S. Ikemizu, and T. Nakayama Critical YxKxHxxxRP Motif in the C-Terminal Region of GATA3 for Its DNA Binding and Function J. Immunol., November 1, 2006; 177(9): 5801 - 5810. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kimura, Y. Ishii, K. Yoh, Y. Morishima, T. Iizuka, T. Kiwamoto, Y. Matsuno, S. Homma, A. Nomura, T. Sakamoto, et al. Overexpression of the Transcription Factor GATA-3 Enhances the Development of Pulmonary Fibrosis Am. J. Pathol., July 1, 2006; 169(1): 96 - 104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Castellano, B. Vire, M. Pion, V. Quivy, D. Olive, I. Hirsch, C. Van Lint, and Y. Collette Active Transcription of the Human FASL/CD95L/TNFSF6 Promoter Region in T Lymphocytes Involves Chromatin Remodeling: ROLE OF DNA METHYLATION AND PROTEIN ACETYLATION SUGGEST DISTINCT MECHANISMS OF TRANSCRIPTIONAL REPRESSION J. Biol. Chem., May 26, 2006; 281(21): 14719 - 14728. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hayashida, M. Oda, K. Ohsawa, A. Yamaguchi, T. Hosozawa, R. M. Locksley, M. Giacca, H. Masai, and S. Miyatake Replication Initiation from a Novel Origin Identified in the Th2 Cytokine Cluster Locus Requires a Distant Conserved Noncoding Sequence J. Immunol., May 1, 2006; 176(9): 5446 - 5454. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Liang, Y. Zhang, D. McDevit, S. Marecki, and B. S. Nikolajczyk The Interleukin-1beta Gene Is Transcribed from a Poised Promoter Architecture in Monocytes J. Biol. Chem., April 7, 2006; 281(14): 9227 - 9237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-Y. Wang, S. Kusam, V. Munugalavadla, R. Kapur, R. R. Brutkiewicz, and A. L. Dent Regulation of Th2 Cytokine Expression in NKT Cells: Unconventional Use of Stat6, GATA-3, and NFAT2 J. Immunol., January 15, 2006; 176(2): 880 - 888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Xue, S. L. Gyles, F. R. Wettey, L. Gazi, E. Townsend, M. G. Hunter, and R. Pettipher Prostaglandin D2 Causes Preferential Induction of Proinflammatory Th2 Cytokine Production through an Action on Chemoattractant Receptor-Like Molecule Expressed on Th2 Cells J. Immunol., November 15, 2005; 175(10): 6531 - 6536. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Martins, A. S. Hutchins, and S. L. Reiner Transcriptional Activators of Helper T Cell Fate Are Required for Establishment but Not Maintenance of Signature Cytokine Expression J. Immunol., November 1, 2005; 175(9): 5981 - 5985. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.-O. Tykocinski, P. Hajkova, H.-D. Chang, T. Stamm, O. SOzeri, M. LOhning, J. Hu-Li, U. Niesner, S. Kreher, B. Friedrich, et al. A Critical Control Element for Interleukin-4 Memory Expression in T Helper Lymphocytes J. Biol. Chem., August 5, 2005; 280(31): 28177 - 28185. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Reiner Epigenetic control in the immune response Hum. Mol. Genet., April 15, 2005; 14(suppl_1): R41 - R46. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. I. Marusina, D.-K. Kim, L. D. Lieto, F. Borrego, and J. E. Coligan GATA-3 Is an Important Transcription Factor for Regulating Human NKG2A Gene Expression J. Immunol., February 15, 2005; 174(4): 2152 - 2159. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Masuda, Y. Yoshikai, H. Kume, and T. Matsuguchi The Interaction between GATA Proteins and Activator Protein-1 Promotes the Transcription of IL-13 in Mast Cells J. Immunol., November 1, 2004; 173(9): 5564 - 5573. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Matsumoto, E. Kubota, Y. Omi, U. Lee, and J. M. Penninger Essential Role of LFA-1 in Activating Th2-Like Responses by {alpha}-Galactosylceramide-Activated NKT Cells J. Immunol., October 15, 2004; 173(8): 4976 - 4984. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Yamashita, M. Ukai-Tadenuma, T. Miyamoto, K. Sugaya, H. Hosokawa, A. Hasegawa, M. Kimura, M. Taniguchi, J. DeGregori, and T. Nakayama Essential Role of GATA3 for the Maintenance of Type 2 Helper T (Th2) Cytokine Production and Chromatin Remodeling at the Th2 Cytokine Gene Loci J. Biol. Chem., June 25, 2004; 279(26): 26983 - 26990. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Wurtz, M. Bajenoff, and S. Guerder IL-4-mediated inhibition of IFN-{gamma} production by CD4+ T cells proceeds by several developmentally regulated mechanisms Int. Immunol., March 1, 2004; 16(3): 501 - 508. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-Y. Pai, M. L. Truitt, and I-C. Ho GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells PNAS, February 17, 2004; 101(7): 1993 - 1998. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Webb, K. I. Matthaei, Y. Cai, A. N. J. McKenzie, and P. S. Foster Polymorphisms in IL-4R{alpha} Correlate with Airways Hyperreactivity, Eosinophilia, and Ym Protein Expression in Allergic IL-13-/- Mice J. Immunol., January 15, 2004; 172(2): 1092 - 1098. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Yoh, K. Shibuya, N. Morito, T. Nakano, K. Ishizaki, H. Shimohata, M. Nose, S. Izui, A. Shibuya, A. Koyama, et al. Transgenic Overexpression of GATA-3 in T Lymphocytes Improves Autoimmune Glomerulonephritis in Mice with a BXSB/MpJ-Yaa Genetic Background J. Am. Soc. Nephrol., October 1, 2003; 14(10): 2494 - 2502. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Franzke, W. Piao, J. Lauber, P. Gatzlaff, C. Konecke, W. Hansen, A. Schmitt-Thomsen, B. Hertenstein, J. Buer, and A. Ganser G-CSF as immune regulator in T cells expressing the G-CSF receptor: implications for transplantation and autoimmune diseases Blood, July 15, 2003; 102(2): 734 - 739. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Soutto, W. Zhou, and T. M. Aune Cutting Edge: Distal Regulatory Elements Are Required to Achieve Selective Expression of IFN-{gamma} in Th1/Tc1 Effector Cells J. Immunol., December 15, 2002; 169(12): 6664 - 6667. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Takemoto, K.-i. Arai, and S. Miyatake Cutting Edge: The Differential Involvement of the N-Finger of GATA-3 in Chromatin Remodeling and Transactivation During Th2 Development J. Immunol., October 15, 2002; 169(8): 4103 - 4107. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Santangelo, D. J. Cousins, N. E. E. Winkelmann, and D. Z. Staynov DNA Methylation Changes at Human Th2 Cytokine Genes Coincide with DNase I Hypersensitive Site Formation During CD4+ T Cell Differentiation J. Immunol., August 15, 2002; 169(4): 1893 - 1903. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Diehl, C.-W. Chow, L. Weiss, A. Palmetshofer, T. Twardzik, L. Rounds, E. Serfling, R. J. Davis, J. Anguita, and M. Rincon Induction of NFATc2 Expression by Interleukin 6 Promotes T Helper Type 2 Differentiation J. Exp. Med., July 1, 2002; 196(1): 39 - 49. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Lavenu-Bombled, C. D. Trainor, I. Makeh, P.-H. Romeo, and I. Max-Audit Interleukin-13 Gene Expression Is Regulated by GATA-3 in T Cells. ROLE OF A CRITICAL ASSOCIATION OF A GATA AND TWO GATG MOTIFS J. Biol. Chem., May 17, 2002; 277(21): 18313 - 18321. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kurata, H.-J. Lee, T. McClanahan, R. L. Coffman, A. O'Garra, and N. Arai Friend of GATA Is Expressed in Naive Th Cells and Functions As a Repressor of GATA-3-Mediated Th2 Cell Development J. Immunol., May 1, 2002; 168(9): 4538 - 4545. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. T. F. Schwenger, R. Fournier, C. C. Kok, V. A. Mordvinov, D. Yeoman, and C. J. Sanderson GATA-3 Has Dual Regulatory Functions in Human Interleukin-5 Transcription J. Biol. Chem., December 14, 2001; 276(51): 48502 - 48509. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kishikawa, J. Sun, A. Choi, S.-C. Miaw, and I-C. Ho The Cell Type-Specific Expression of the Murine IL-13 Gene Is Regulated by GATA-3 J. Immunol., October 15, 2001; 167(8): 4414 - 4420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Nawijn, G. M. Dingjan, R. Ferreira, B. N. Lambrecht, A. Karis, F. Grosveld, H. Savelkoul, and R. W. Hendriks Enforced Expression of GATA-3 in Transgenic Mice Inhibits Th1 Differentiation and Induces the Formation of a T1/ST2-Expressing Th2-Committed T Cell Compartment In Vivo J. Immunol., July 15, 2001; 167(2): 724 - 732. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Cakouros, P. N. Cockerill, A. G. Bert, R. Mital, D. C. Roberts, and M. F. Shannon A NF-{{kappa}}B/Sp1 Region Is Essential for Chromatin Remodeling and Correct Transcription of a Human Granulocyte- Macrophage Colony-Stimulating Factor Transgene J. Immunol., July 1, 2001; 167(1): 302 - 310. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
