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Cutting Edge |
Loci Accompany Th1/Th2 Differentiation
* Section of Immunobiology, Yale University School of Medicine, and
Howard Hughes Medical Institute, New Haven, CT 06520
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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and IL-4
loci during Th1/Th2 differentiation. These changes in histone
acetylation status are locus and lineage specific, and are maintained
by the transcription factors Tbet and GATA3 in a STAT-dependent manner.
Our results suggest a model of cytokine locus activation in which TCR
signals initiate chromatin remodeling and locus opening in a
cytokine-independent fashion. Subsequently, cytokine signaling
reinforces polarization by expanding and maintaining the accessible
state at the relevant cytokine locus (IL-4 or
IFN-). In this model, GATA3 and Tbet serve as
transcriptional maintenance factors, which keep the locus accessible to
the transcriptional machinery. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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production and Th1 development (7). GATA3 and Tbet may be
"master regulators" of Th lineage determination. Both act as
transactivators, can induce DNase I hypersensitivity changes in the
cytokine loci, and possess negative regulatory functions; GATA3
inhibits IFN- expression, and Tbet inhibits Th2 cytokine expression
(7, 8, 9, 10).
Epigenetic events are important determinants of cytokine gene
expression and lineage commitment. Selective changes in DNase I
hypersensitivity and methylation in the IL-4 and
IFN- loci accompany Th differentiation (11, 12). Also, repositioning of the IL-4 or
IFN- loci to areas of silencing within the nucleus occurs
during Th1 or Th2 differentiation, respectively (13). A
causative relationship between chromatin remodeling and Th cell
differentiation has not yet been established. The study of other events
more closely tied to transcriptional regulation, such as enzymatic
modification of histone proteins, might aid in our understanding of
such a relationship.
Histones undergo an array of posttranslational modifications on tail domains, including acetylation, phosphorylation, and methylation (14). These modifications, as well as the primary sequence of the histone tails themselves, are highly conserved from yeast to man and have been closely linked to biological events (e.g., replication, transcription, and silencing). High levels of histone acetylation at particular loci correlate with transcriptional activity (15), whereas reduced levels correlate with silencing (16). Factors mediating acetylation and deacetylation serve as transcriptional coactivators and corepressors, respectively, suggesting a causative relationship between acetylation and transcription (17, 18).
We show that histones in the cytokine loci of naive T cells are unacetylated. Upon TCR stimulation, the loci are rapidly and progressively acetylated on histones H3 and H4. Early acetylation occurs in the IL-4 locus irrespective of polarizing conditions, correlating with early transcription. The maintenance of acetylation depends on cytokine/STAT signaling. Tbet and GATA3 also contribute to the polarized acetylated state.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Four- to 8-wk-old C57BL/6J, BALB/c, STAT6-/-, and STAT4-/- mice were purchased from The Jackson Laboratory (Bar Harbor, ME) and maintained in the Yale University Animal Resources Center (New Haven, CT).
In vitro T cell differentiation
Naive CD62LhighCD44lowCD4+ T cells were purified by flow cytometric cell (FACS) sorting as previously described (19). These cells were either used directly in chromatin immunoprecipitation (ChIP2; naive samples) or stimulated in 24-well plates under polarizing conditions as described with 1 µg/ml anti-CD3 mAb (145-2C11; American Type Culture Collection, Manassas, VA) plus 1 µg/ml anti-CD28 (37.5.1; American Type Culture Collection) (19). T cells were expanded under the same conditions as the primary cultures. Cytokines were measured (ELISA) from 2 x 105 T cells restimulated for 24 h by plate-bound anti-CD3 (1 µg/ml) plus anti-CD28 (2 µg/ml).
ChIP
For ChIP analysis, 0.5–1.5 x 107 T cells were fixed with 1% formaldehyde for 10 min at 37°C, washed with PBS, and lysed in ChIP lysis buffer (Upstate Biotechnology, Lake Placid, NY). DNA was sonicated by pulsing three to six times. Anti-acetylated histone H3 or H4 was added (4 µl per immunoprecipitation) and incubated overnight. Protein A-agarose beads (Upstate Biotechnology) were added for 1 h then washed once each with low-salt buffer, high-salt buffer, and LiCl buffer, and twice with TE (buffer ingredients are available in the Upstate Biotechnology catalog). Beads were eluted with 0.1 M NaHCO3 and 1% SDS, and cross-links were reversed at 65°C. DNA was ethanol-precipitated in the presence of 20 µg glycogen. Aliquots of equal volume from each sample were used as input controls.
Polymerase chain reaction
PCR was performed on chromatin samples for 28 cycles under standard reaction conditions. Real-time quantitative PCR was performed using an icycler iQ (Bio-Rad, Hercules, CA). Samples were normalized against standard sheared input DNA. Concentrations were determined using the software provided by the manufacturer.
PCR primer sequences (Keck Oligonucleotide Synthesis Facility, Yale
University) were as follows: IL-4P, 5'-ACTCATTTTCCCTTGGTTTCAGC-3'
and 5'-GATTTTTGTCGCATCCGTGG-3'; IFN-P,
5'-CGTAATCCCGAGGAGCCTTC-3' and 5'-CTTTCAATGACTGTGCCGTGG-3';
intronic enhancer (IE), 5'-TCTGCTTGGACATCTCTCTTCCC and
5'-ACCACCCCACAGGTCTTTGTTC-3'; hypersensitive site (HSS),
5'-TTGGGGACAGAGGATGCCTTAC-3' and 5'-GCCTTGCTGAGAGTTTCTTTTGC-3';
TCR
enhancer, 5'-AGATAGTGAATCAATAGCCAG-3' and
5'-TTCAAAGGGGGACCTGTTT-3'.
Real-time PCR sequences were as follows: IL-4P,
5'-TCTTGATAAACTTAATTGTCTCTCGTCAC-3' and
5'-GCAGGATGACAACTAGCTGGG-3'; IFN-P, 5'-TCAGCTGATCCTTTGGACCC-3'
and 5'-CTCAGAGCTAGGCCGCAGG-3'.
Fluorogenic probes (Biosearch Technologies, Novato, CA) were as
follows: IL-4P, 5'-ACGGGACAGAGCTATTGATGGGTCTCA-3'; IFN-P,
5'-CTGACTTGAGACAGAAGTTCTGGGCTTCTCC-3'.
Retroviral transduction
Retroviral transduction of T cells was performed as described (20). Retroviral vectors (K. Murphy, Washington University, St. Louis, MO, and L. Glimcher, Harvard University, Boston, MA), allowed expression of GATA3 or Tbet plus enhanced green fluorescent protein (eGFP) (7, 21). At 24 h after stimulation, cells were infected with retroviral supernatant. At days 5–6, cells were sorted into eGFP-negative and eGFP-positive populations, expanded for 4 days, and either restimulated or used in ChIP experiments. The Phoenix-ECO packaging cell line was a gift of Dr. G. Nolan (Stanford University, Palo Alto, CA).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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loci in naive and effector Th cells was assessed using ChIP with Abs
specific for acetylated histones H3 or H4. We analyzed the IL-4 and
IFN- promoter regions (IL-4P and IFN-P) as well as two
IL-4 locus regulatory regions, the DNase I HSS (CNS-1) and
the IE (HS2) (11, 22). These regions coordinately function
as enhancers in the IL-4 locus (19, 23). In
naive cells, low levels of IL-4P, IFN-P, HSS, or IE were
coimmunoprecipitated with acetylated histones H3 or H4. In contrast,
both H3 and H4 acetylation were substantially greater in day 6 Th1 and
Th2 effectors (Fig. 1
, A and
B). In Th1 cells, IFN-P, but not the IL-4
locus, was hyperacetylated. Conversely, in Th2 cells, the IL-4
regulatory regions were hyperacetylated, whereas IFN-P was not.
These acetylation changes persisted in cells rested for 14 days,
conditions where no cytokine transcription occurred (data not shown).
Acetylation changes appeared to affect the entire IL-4
locus, because identical patterns were observed at distal sites,
including the region of the IL-5 gene (data not shown).
Input controls demonstrated that equivalent amounts of material were
added to each immunoprecipitation (Fig. 1C). As an
immunoprecipitation control, TCR enhancer acetylation was analyzed.
Identical results were observed in
C57BL/6 (Fig. 1), BALB/c (Figs. 2 and 3),
and AND TCR-transgenic mice (data not shown), establishing the
generality of the findings. Identical patterns of H3 and H4
acetylation suggested that their regulation in the cytokine loci might
be similar. Subsequent studies focused on H3 acetylation.
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A).
IL-4P acetylation was also observed in Th1-cultured cells at day 2,
decreasing by day 6. This observation correlates with early and
transient differentiation condition-independent IL-4 transcription
(13, 24). Similar patterns at IE and HSS were observed
(data not shown). IFN-P acetylation patterns resembled those of the
IL-4 locus (Fig. 2B). Acetylation increases were
detectable under both polarizing conditions as early as day 1 (data not
shown). Acetylation continued to increase after day 2 in Th1 cultures
while decreasing over time in Th2 cultures (Fig. 2B). Unlike
the IL-4 locus, acetylation at the IFN- locus
in Th2 cells was substantially less than that in Th1 cells at all time
points examined. Early and non-lineage-specific IFN- transcription
also occurs, but with earlier and more transient kinetics
(13). The "window" of acetylation in the
IFN- locus may be transient and thus was less prominent
in these studies. The reduction in acetylation could reflect active
deacetylation under opposite polarizing conditions or selection of a
population that fails to maintain an acetylated locus. The
earliest phase of locus activation occurs independently of cytokine
signaling and might be mediated by nonspecific entities triggered by
TCR/CD28 stimulation, such as chromatin remodeling complexes
(25).
IFN-P and IL-4P acetylation was significantly lower in STAT4- and
STAT6-deficient T cells cultured under Th1 or Th2 conditions (Fig. 3, A–C). Acetylation never reached levels observed
in wild-type cells, even after restimulation (Figs. 2 and 3E). Interestingly, IL-4P acetylation was significantly
increased in Th1-cultured, STAT4-deficient T cells (Fig. 3, B and E). Likewise, IFN-P was hyperacetylated
in Th2-cultured, STAT6-deficient T cells (Fig. 3, C and
E). Thus, STAT signaling (i.e., IL-12, IL-4) might
negatively affect Th1 or Th2 development by inhibiting cytokine loci
accessibility. In the absence of STAT signaling, IL-4 or
IFN- loci hyperacetylation and transcription proceeded
under normally suppressive conditions (Th1 or Th2, respectively). The
mechanism by which this cross-regulation occurs is unknown. One
possibility is that it is mediated by the coactivators, GATA3 and Tbet,
because extinction of their expression is mediated by IL-12 and IL-4,
respectively (8, 26). When restimulated, STAT6-deficient T
cells cultured under Th2 conditions and STAT4-deficient T cells
cultured under Th1 conditions produced detectable amounts of IFN-
and IL-4, respectively (Fig. 3F), consistent with
earlier reports (2, 27). These results indicate that the
polarizing cytokine milieu can specify cytokine expression in two ways.
First, STAT function can maintain cytokine locus accessibility. Second,
STATs can inhibit locus accessibility of the opposing cytokine. Whether
these putative functions are mediated by direct STAT binding or
indirectly by STAT-induced factors remains to be determined.
GATA3 and Tbet are activators of IL-4 and IFN- production,
respectively. To determine whether these factors affect cytokine locus
acetylation, we introduced by retroviral transduction GATA3 or Tbet
into STAT6- or STAT4-deficient T cells cultured under Th2 or Th1
conditions, respectively. Transduction of empty virus into STAT6
knockout T cells had no effect on IL-4 locus acetylation
(Fig. 4A). In contrast, GATA3
significantly enhanced acetylation in the locus (Fig. 4A,
lower panel). These data correlate with IL-4 transcription
in GATA-transduced cells (20, 21). GATA3 induced a slight
decrease in acetylation of IFN-P (Fig. 4A) while also
reducing IFN- expression (8). Tbet induced a small but
reproducible increase (2- to 3-fold) in IFN-P acetylation (Fig. 4B), consistent with an ability to induce IFN- expression
(7, 9). In contrast, Tbet did not affect IL-4P
acetylation, despite a strong inhibitory effect on IL-4 production (10-
to 50-fold; Ref. 7 and data not shown). These results were
confirmed by real-time PCR analysis (Fig. 4, C and
D). Thus, GATA3 and Tbet appear to have a direct effect on
acetylation of the IL-4 and IFN- loci in the
absence of STAT6 and STAT4 signaling. We have not addressed the likely
possibility that GATA3 and Tbet might cooperate with other factors,
such as NFAT or STATs, to induce optimal IL-4 and
IFN- locus acetylation and transcription.
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, where activation-induced acetylation is restricted
to promoter-proximal nucleosomes (28). Second,
IL-4 and IFN- loci acetylation persists when
there is little if any transcription. In contrast, IFN-
locus acetylation occurs during acute stimulation and rapidly
dissipates upon loss of the stimulus (28). Thus,
acetylation in the IL-4 and IFN- loci
correlates more closely with transcriptional competence than with acute
transcriptional activity, reminiscent of the -globin locus
(15). We postulate that this type of acetylation
(widespread and persistent) is a mark of differentiation rather than of
transcriptional activation.
Our data support a multistep model of IL-4 and
IFN- gene activation whereby locus accessibility (as
measured by histone acetylation) regulates cytokine expression
(29). In the first step, T cell activation results in
acetylation (and transcription) of IL-4 and, to a lesser
degree, IFN-, irrespective of the cytokine environment.
This phase is likely mediated by signals generated by TCR/CD28
stimulation. Maintenance and expansion of the accessibility of the
relevant cytokine locus, as well as suppressive events preventing the
expression of the opposing cytokine, combine to reinforce polarized
Th1/Th2 populations. Positive and negative regulation is mediated by
STAT proteins as well as GATA3 and Tbet.
Thus, T cell differentiation is characterized by dynamic changes in cytokine locus histone acetylation. Upon initial T cell stimulation, these changes enable early transcription of cytokines, possibly contributing to the cytokine milieu in which T cell differentiation can proceed. Second, they help to establish heritable and stable patterns of cytokine locus accessibility in effector cells, enabling rapid and robust secondary responses. Maintained acetylation would also provide locus and lineage specificity, because transcription factor binding would highly favor an acetylated locus.
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Footnotes |
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2 Abbreviations used in this paper: ChIP, chromatin immunoprecipitation; GFP, green fluorescent protein; eGFP, enhanced GFP; HSS, hypersensitive site; IE, intronic enhancer.
Received for publication March 13, 2002. Accepted for publication May 23, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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-globin chromosomal domain. EMBO J. 13:1823.[Medline]
inhibits Th type 2 development through inhibition of GATA-3 expression. J. Immunol. 165:4773.-producing CD4+ T cells following activation of naive CD4+ T cells. J. Immunol. 158:1085.[Abstract]
promoter. Cell 103:667.[Medline]
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M. Long, A. M. Slaiby, A. T. Hagymasi, M. A. Mihalyo, A. C. Lichtler, S. L. Reiner, and A. J. Adler T-bet Down-Modulation in Tolerized Th1 Effector CD4 Cells Confers a TCR-Distal Signaling Defect That Selectively Impairs IFN-{gamma} Expression J. Immunol., January 15, 2006; 176(2): 1036 - 1045. [Abstract] [Full Text] [PDF]
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A. Baguet, X. Sun, T. Arroll, A. Krumm, and M. Bix Intergenic Transcription Is Not Required in Th2 Cells to Maintain Histone Acetylation and Transcriptional Permissiveness at the Il4-Il13 Locus J. Immunol., December 15, 2005; 175(12): 8146 - 8153. [Abstract] [Full Text] [PDF]
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S. Chang and T. M. Aune Histone hyperacetylated domains across the Ifng gene region in natural killer cells and T cells PNAS, November 22, 2005; 102(47): 17095 - 17100. [Abstract] [Full Text] [PDF]
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M. Yamashita, R. Shinnakasu, H. Asou, M. Kimura, A. Hasegawa, K. Hashimoto, N. Hatano, M. Ogata, and T. Nakayama Ras-ERK MAPK Cascade Regulates GATA3 Stability and Th2 Differentiation through Ubiquitin-Proteasome Pathway J. Biol. Chem., August 19, 2005; 280(33): 29409 - 29419. [Abstract] [Full Text] [PDF]
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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]
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Y.-K. Jee, J. Gilmour, A. Kelly, H. Bowen, D. Richards, C. Soh, P. Smith, C. Hawrylowicz, D. Cousins, T. Lee, et al. Repression of Interleukin-5 Transcription by the Glucocorticoid Receptor Targets GATA3 Signaling and Involves Histone Deacetylase Recruitment J. Biol. Chem., June 17, 2005; 280(24): 23243 - 23250. [Abstract] [Full Text] [PDF]
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 S. L. Reiner Epigenetic control in the immune response Hum. Mol. Genet., April 15, 2005; 14(suppl_1): R41 - R46. [Abstract] [Full Text] [PDF]
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R. M. Thomas, L. Gao, and A. D. Wells Signals from CD28 Induce Stable Epigenetic Modification of the IL-2 Promoter J. Immunol., April 15, 2005; 174(8): 4639 - 4646. [Abstract] [Full Text] [PDF]
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T. Valineva, J. Yang, R. Palovuori, and O. Silvennoinen The Transcriptional Co-activator Protein p100 Recruits Histone Acetyltransferase Activity to STAT6 and Mediates Interaction between the CREB-binding Protein and STAT6 J. Biol. Chem., April 15, 2005; 280(15): 14989 - 14996. [Abstract] [Full Text] [PDF]
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Y. Tong, T. Aune, and M. Boothby T-bet antagonizes mSin3a recruitment and transactivates a fully methylated IFN-{gamma} promoter via a conserved T-box half-site PNAS, February 8, 2005; 102(6): 2034 - 2039. [Abstract] [Full Text] [PDF]
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H. Kusaba, P. Ghosh, R. Derin, M. Buchholz, C. Sasaki, K. Madara, and D. L. Longo Interleukin-12-induced Interferon-{gamma} Production by Human Peripheral Blood T Cells Is Regulated by Mammalian Target of Rapamycin (mTOR) J. Biol. Chem., January 14, 2005; 280(2): 1037 - 1043. [Abstract] [Full Text] [PDF]
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D. U. Lee and A. Rao Molecular analysis of a locus control region in the T helper 2 cytokine gene cluster: A target for STAT6 but not GATA3 PNAS, November 9, 2004; 101(45): 16010 - 16015. [Abstract] [Full Text] [PDF]
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T. Katsumoto, M. Kimura, M. Yamashita, H. Hosokawa, K. Hashimoto, A. Hasegawa, M. Omori, T. Miyamoto, M. Taniguchi, and T. Nakayama STAT6-Dependent Differentiation and Production of IL-5 and IL-13 in Murine NK2 Cells J. Immunol., October 15, 2004; 173(8): 4967 - 4975. [Abstract] [Full Text] [PDF]
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A. Morinobu, Y. Kanno, and J. J. O'Shea Discrete Roles for Histone Acetylation in Human T Helper 1 Cell-specific Gene Expression J. Biol. Chem., September 24, 2004; 279(39): 40640 - 40646. [Abstract] [Full Text] [PDF]
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J. H. Bream, D. L. Hodge, R. Gonsky, R. Spolski, W. J. Leonard, S. Krebs, S. Targan, A. Morinobu, J. J. O'Shea, and H. A. Young A Distal Region in the Interferon-{gamma} Gene Is a Site of Epigenetic Remodeling and Transcriptional Regulation by Interleukin-2 J. Biol. Chem., September 24, 2004; 279(39): 41249 - 41257. [Abstract] [Full Text] [PDF]
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M. Yamashita, R. Shinnakasu, Y. Nigo, M. Kimura, A. Hasegawa, M. Taniguchi, and T. Nakayama Interleukin (IL)-4-independent Maintenance of Histone Modification of the IL-4 Gene Loci in Memory Th2 Cells J. Biol. Chem., September 17, 2004; 279(38): 39454 - 39464. [Abstract] [Full Text] [PDF]
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M. Shnyreva, W. M. Weaver, M. Blanchette, S. L. Taylor, M. Tompa, D. R. Fitzpatrick, and C. B. Wilson Evolutionarily conserved sequence elements that positively regulate IFN-{gamma} expression in T cells PNAS, August 24, 2004; 101(34): 12622 - 12627. [Abstract] [Full Text] [PDF]
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A. Baguet and M. Bix Chromatin landscape dynamics of the Il4-Il13 locus during T helper 1 and 2 development PNAS, August 3, 2004; 101(31): 11410 - 11415. [Abstract] [Full Text] [PDF]
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C. M. Tato, G. A. Martins, F. A. High, C. B. DiCioccio, S. L. Reiner, and C. A. Hunter Cutting Edge: Innate Production of IFN-{gamma} by NK Cells Is Independent of Epigenetic Modification of the IFN-{gamma} Promoter J. Immunol., August 1, 2004; 173(3): 1514 - 1517. [Abstract] [Full Text] [PDF]
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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]
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M. Inami, M. Yamashita, Y. Tenda, A. Hasegawa, M. Kimura, K. Hashimoto, N. Seki, M. Taniguchi, and T. Nakayama CD28 Costimulation Controls Histone Hyperacetylation of the Interleukin 5 Gene Locus in Developing Th2 Cells J. Biol. Chem., May 28, 2004; 279(22): 23123 - 23133. [Abstract] [Full Text] [PDF]
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 G. S. Eisenbarth and P. A. Gottlieb Autoimmune Polyendocrine Syndromes N. Engl. J. Med., May 13, 2004; 350(20): 2068 - 2079. [Full Text] [PDF]
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B. Lu, P. Zagouras, J. E. Fischer, J. Lu, B. Li, and R. A. Flavell Kinetic analysis of genomewide gene expression reveals molecule circuitries that control T cell activation and Th1/2 differentiation PNAS, March 2, 2004; 101(9): 3023 - 3028. [Abstract] [Full Text] [PDF]
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W. Zhou, S. Chang, and T. M. Aune From the Cover: Long-range histone acetylation of the Ifng gene is an essential feature of T cell differentiation PNAS, February 24, 2004; 101(8): 2440 - 2445. [Abstract] [Full Text] [PDF]
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H. Nakajima, A. Asai, A. Okada, L. Ping, F. Hamajima, T. Sata, and K. Isobe Transcriptional Regulation of ILT Family Receptors J. Immunol., December 15, 2003; 171(12): 6611 - 6620. [Abstract] [Full Text] [PDF]
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J. L. Grogan, Z.-E. Wang, S. Stanley, B. Harmon, G. G. Loots, E. M. Rubin, and R. M. Locksley Basal Chromatin Modification at the IL-4 Gene in Helper T Cells J. Immunol., December 15, 2003; 171(12): 6672 - 6679. [Abstract] [Full Text] [PDF]
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D. B. Stetson, M. Mohrs, R. L. Reinhardt, J. L. Baron, Z.-E. Wang, L. Gapin, M. Kronenberg, and R. M. Locksley Constitutive Cytokine mRNAs Mark Natural Killer (NK) and NK T Cells Poised for Rapid Effector Function J. Exp. Med., October 6, 2003; 198(7): 1069 - 1076. [Abstract] [Full Text] [PDF]
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J. Y. Cho, V. Grigura, T. L. Murphy, and K. Murphy Identification of cooperative monomeric Brachyury sites conferring T-bet responsiveness to the proximal IFN-{gamma} promoter Int. Immunol., October 1, 2003; 15(10): 1149 - 1160. [Abstract] [Full Text] [PDF]
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S. Yano, P. Ghosh, H. Kusaba, M. Buchholz, and D. L. Longo Effect of Promoter Methylation on the Regulation of IFN-{gamma} Gene During In Vitro Differentiation of Human Peripheral Blood T Cells into a Th2 Population J. Immunol., September 1, 2003; 171(5): 2510 - 2516. [Abstract] [Full Text] [PDF]
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J. Liu and D. I. Beller Distinct Pathways for NF-{kappa}B Regulation Are Associated with Aberrant Macrophage IL-12 Production in Lupus- and Diabetes-Prone Mouse Strains J. Immunol., May 1, 2003; 170(9): 4489 - 4496. [Abstract] [Full Text] [PDF]
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B. Adkins, T. Williamson, P. Guevara, and Y. Bu Murine Neonatal Lymphocytes Show Rapid Early Cell Cycle Entry and Cell Division J. Immunol., May 1, 2003; 170(9): 4548 - 4556. [Abstract] [Full Text] [PDF]
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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]
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