Cellular & Molecular Immunology 15
GATA-3 – Not Just for Th2 Cells Anymore
I-Cheng Ho1 and Sung-Yun Pai2
GATA-3 was first cloned as a T cell specific transcription factor in 1991 and its importance in the transcriptional
control of T helper type 2 cell (Th2) differentiation was established in the mid to late 90’s. A role for GATA-3
during thymic development has long implied by its continuous and regulated expression through out T lineage
development, but the absolute requirement for GATA-3 during early T lymphoid commitment/survival previously
precluded definitive answers to this question. Several technical breakthroughs have fueled fruitful investigation in
recent years and uncovered unexpected and critical roles for GATA-3 in CD4 thymocyte survival, invariant natural
killer T cell generation and function, and also in beta selection. Not only does GATA-3 participate in nearly every
stage of T cell development from common lymphoid progenitor to Th2, conditional knockout studies have indicated
that the influence of GATA-3 also extends beyond the immune system. Cellular & Molecular Immunology. 2007;
Key Words: GATA-3, T cell, transcription factor, thymocyte
The development of pluripotent progenitors into
differentiated effector cells relies on the ordered execution of
distinct transcriptional programs. In the case of binary
differentiation steps, lineage specific transcription factors,
upregulated in response to external differentiation signals,
evoke patterns of gene expression that drive cells into one
lineage and suppress programs associated with the opposite
lineage. Hematopoietic stem cells that mature into T
lymphocytes must traverse several such binary branchpoints,
including the T vs B, CD4 vs CD8, and T helper type 1 (Th1)
vs T helper type 2 (Th2) decision steps. The last example, in
which naïve precursor helper T cells differentiate into
polarized T helper cell subsets with distinct cytokine
production profiles and effector functions, has been the
subject of intense study, resulting in a model in which the
transcription factor T-bet drives Th1 differentiation, while the
Volume 4 Number 1 February 2007
transcription factor GATA-3 drives Th2 differentiation (1, 2).
In recent years the lineage specific transcription factor model
has been extended by the identification of FoxP3 and RORγt
as “master regulators” of naturally occurring T regulatory
(Treg) and T helper type 17 (Th17) cells respectively (3, 4).
Our understanding of the Th2 master regulator GATA-3
has increased substantially, thanks to several technical
breakthroughs, such as reaggregate fetal thymic organ culture,
siRNA technology, retroviral transduction of primary T cells,
and the generation of conditionally deficient mice. Unlike
T-bet, whose tissue expression is limited to the immune
system and which plays little role during early T progenitor
or thymic development (5, 6), GATA-3 has emerged as
having multiple roles in the earlier stages of T lymphoid and
in non-immune cell development. Here we summarize the
evidence that GATA-3 is not only a critical and essential
regulator of Th2 cell development and function, but also of
CD4 T cell survival, invariant natural killer T cell
development and function, and T commitment. How a single
transcription factor that is continuously expressed during T
lymphoid development can perform different functions at
each stage has yet to be understood. Our growing
understanding of the interacting partners, post-translational
modification and known direct targets of GATA-3 may
elucidate the molecular mechanisms of transcriptional
regulation in future years.
GATA-3 and the GATA family of transcription
GATA-3 is a member of the GATA family of transcription
factors (7). There are at least 6 GATA proteins, GATA-1 to
1Division of Rheumatology, Immunology, and Allergy, Department of
Medicine, Brigham and Women’s Hospital, Harvard Medical School,
Boston, MA 02115, USA;
2Department of Pediatric Hematology-Oncology, Children's Hospital Boston
and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
3Corresponding to: Dr. I-Cheng Ho, Smith Building, Room 526D, One
Jimmy Fund Way, Boston, MA 02115, USA. Tel: +01-617-525-1005, Fax:
+01-617-525-1010, E-mail: firstname.lastname@example.org
Received Feb 12, 2007. Accepted Feb 22, 2007.
Copyright © 2007 by The Chinese Society of Immunology
16 GATA-3 – Not Just for Th2 Cells Anymore
Volume 4 Number 1 February 2007
GATA-6, that have been identified in mammalian genome.
All GATA proteins contain two highly conserved C2C2 type
zinc fingers, which can bind to DNA containing the
consensus WGATAR sequence (W = A or T and R = A or G),
and are functionally interchangeable in some in vitro systems
(8, 9). The GATA members can be further divided into two
main groups based on their tissue distribution in adult
animals. GATA-1, GATA-2, and GATA-3 are expressed
mainly in hematopoietic cells, whereas GATA-4, GATA-5,
and GATA-6 are found in endoderm-derived tissues/organs,
such as heart and intestine. GATA-1, the founding member of
the GATA family, is expressed mainly in erythroid/
megakaryocytic cells in adult animals, and was cloned based
on its ability to bind to a functionally critical GATA sequence
in regulatory regions of the α and β-globin gene clusters (10).
The finding that several conserved and functionally
important GATA binding sequences were also identified in
the enhancers of the T cell receptor (TCR) genes suggested
the presence of a GATA-1-like transcription factor that is
expressed in T cells. By screening T cell cDNA libraries with
the zinc finger region of GATA-1 under low stringency
conditions, several groups independently cloned GATA-3 as
the T cell-specific GATA member (11-13). Although GATA-3
is nearly exclusively expressed in T cells in adult animals, its
expression can be detected in non-hematopoietic tissues/
organs, such as central nervous system, skin, inner ear,
mammary glands, and kidney, during embryogenesis (14-18).
Indeed the critical role of GATA-3 during embryogenesis is
underscored by the fact that mice deficient in GATA-3 die at
embryonic day 11.5 (19) and that haploinsufficiency of
GATA-3 in human results in HDR syndrome, characterized
by hypoparathyroidism, deafness, and renal dysplasia (20,
GATA-3 and control of Th differentiation
The first described function of GATA-3 in the immune
system is as a Th2 specific transcription factor, and the
transcriptional regulation of Th subset differentiation has
been the subject of a number of excellent reviews (1-4). This
section will focus on recent in vivo confirmation of the role
of GATA-3 as master regulator of Th2 differentiation and
Introduction to Th subsets
The differentiation of naïve CD4 T cells into Th1 and Th2
cells was a phenomenon described more than two decades
ago (22, 23). Each subset has a set of signature cytokines and
effector functions. Th1 cells produce mainly IFN-γ and are
responsible for eradicating intracellular microorganisms,
whereas Th2 cells express IL-4, IL-5, and IL-13, and
orchestrate immunity against
Unregulated Th1 function is pathogenic in many autoimmune
diseases, such as type 1 diabetes mellitus, rheumatoid
arthritis, or inflammatory bowel disease, whereas unbalanced
Th2 function causes allergic inflammation. Two new
functional subsets, Th17 and Treg cells, are also derived from
CD4 single positive (SP) thymocytes (24-28). The signature
cytokines of Th17 cells are IL-17, IL-17F, and IL-22. IL-17
is critical for eliminating extracellular bacteria (29). Th1, Th2,
and Th17 cells can initiate or augment immune responses and
are therefore generally referred to as effector Th cells. In
contrast, Treg cells produce high level of anti-inflammatory
cytokines, such as IL-10 and/or TGF-β, and transdominantly
inhibit the proliferation and function of effector Th cells.
In the case of Th1 and Th2 cells, after initial upregulation
of both Th1 and Th2 specific factors, certain costimulatory
molecules, types of antigen presenting cells (APC), or doses
of antigen, and most importantly, the cytokine milieu
conspire to promote the dominant expression of either T-bet
or GATA-3 and suppression of the factor responsible for the
alternate fate, exemplifying the binary lineage decision
process. Thus triggering IL-4/Stat6 signaling promotes and is
required for Th2 development whereas IFN-γ/Stat1 and
IL-12/Stat4 signaling are critical for the differentiation of
Th1 cells. The cytokine milieu is critical also for the
differentiation of Th17 cells, which requires IL-6 and TGF-β,
while TGF-β alone promotes the differentiation of Treg cells.
Whereas previously, the subsets of Th cells were primarily
identified by their functional cytokine production profile,
each subset can now be linked with a key lineage-specific
transcription factor (T-bet, GATA-3, RORγt, FoxP3), that is
both necessary and sufficient to drive development, and
serves as a marker of subset identity (Th1, Th2, Th17, Treg).
Conditional knockout studies confirm GATA-3 as a “master
regulator” of Th2 differentiation
GATA-3 was suspected to be important in Th2 differentiation
based first on the discovery that GATA-3 binds cognate sites
in the IL-5 promoter (30) and then its differential expression
in Th2 cells compared to Th1 cells (31, 32). Upregulation of
GATA-3 from the low levels normally expressed in naïve Th
cells requires both TCR signals and exposure to IL-4, the
most potent Th2-polarizing cytokine, whose main action is
activation of Stat6. Remarkably, forced expression of
GATA-3 is sufficient to induce the production of type 2
cytokines in cells lacking Stat6 and in the presence of IFN-γ
and depletion of IL-4, a cytokine milieu that ordinarily drives
Th1 differentiation (33-35). Taken together, these results
indicate that GATA-3 is a downstream target gene of
IL-4/Stat6 but, once induced, is sufficient to drive the
expression of Th2 cytokines in an IL-4/Stat6-independent
Studies of GATA-3 transgenic mice further support the
notion that GATA-3 is sufficient to promote the
differentiation and function of Th2 cells. Th cells obtained
from GATA-3 transgenic mice already express a high level of
T1/ST2, an IL-1R family member that is preferentially
expressed on the surface of murine Th2 cells, and continue to
produce type 2 cytokines even after cultivation under Th1
polarizing conditions (36). In several in vivo models, such as
airway allergic inflammation, worm infection, or delayed
type hypersensitivity, GATA-3 transgenic mice exhibit
augmented Th2 immune responses and reciprocally display
Cellular & Molecular Immunology 17
Volume 4 Number 1 February 2007
attenuated Th1 responses (37-40).
GATA-3 is not only sufficient to direct the differentiation
of Th cells into the Th2 pathway, but earlier studies indicated
that GATA-3 is also essential for the differentiation and
function of Th2 cells. Anti-sense GATA-3 RNA has been
shown to suppress the expression of IL-4 and/or IL-5 in Th2
cells (31, 41). In addition, nasal administration of anti-sense
GATA-3 oligonucleotides suppressed the expression of
GATA-3 and significantly attenuated allergic airway
inflammation in an animal model of asthma (42). A
“dominant negative” GATA-3 mutant has also been used to
suppress the function of GATA-3 in transgenic models (43,
44). These KRR GATA-3 transgenic mice are more resistant
to Th2 cell-mediated allergic airway inflammation and Th
cells derived from these mice produce less type 2 cytokines
than wild type cells. However, the KRR GATA-3 is not a true
dominant negative mutant and also affects the proliferation
and homing of the transgenic Th cells (45). Some of the
features are probably caused by artifacts of overexpressing
the KRR mutant instead of suppressing the function of
endogenous wild type GATA-3.
Because germline deletion of GATA-3 results in
embryonic lethality (19), confirmation of the essential role of
GATA-3 in the differentiation and function of Th2 cells in
whole animals required the generation of mice conditionally
deficient in GATA-3 using the Cre-lox system. Two groups
generated such mice independently. In one model, henceforth
called G3-lckCre mice, GATA-3 was deleted using Cre
recombinase driven by the proximal lck promoter. These Th
cells exhibit a defect in differentiating into Th2 cells (46). In
addition, the GATA-3 deficient Th cells, differentiated under
Th2 polarizing conditions, often produce more IFN-γ than
wild type Th1 cells. The inability of the GATA-3-deficient Th
cells to produce type 2 cytokines does not originate from
defects during thymic development because similar results
were obtained when the GATA-3 gene was deleted in Th
cells in vitro with a retroviral Cre recombinase. These results
were confirmed in a second model using Cre recombinase
driven by OX40 promoter, which is expressed only after
activation of mature CD4 T cells, bypassing thymic
development (47). In addition to impaired cytokine
production, GATA-3-deficient Th2 cells also proliferated less
robustly than wild type Th2 cells (47).
The effect of GATA-3 deficiency is also observed in both
mice and humans in vivo. When GATA-3 deficient mice were
immunized with an antigen mixed with alum, Th cells
derived from draining lymph nodes produced very little IL-4
but an abnormally high level of IFN-γ in response to
rechallenge with the antigen (46). This was in sharp contrast
to likewise immunized wild type mice, which mounted a Th2
immune response. When GATA-3 deficient mice were
infected with N. brasilienesis, which usually induces a
dominant Th2 immune response, the mice had a reduced
level of serum IgE, and the blasting Th cells harvested from
these mice displayed a cytokine profile of Th1 cells instead
of Th2 cells (47). Furthermore, human individuals, who carry
only one functional GATA-3 allele and suffer from HDR
syndrome, have a reduced serum level of Th2-dependent
immunoglobulins, such as IgG4 and IgE, whereas the level of
Th1-dependent IgG1 is reciprocally elevated (48). These
results firmly establish the essential role of GATA-3 in
regulating the differentiation of Th2 cells.
Transcriptional targets of GATA-3 in Th cells
It stands to reason that GATA-3 would have characteristic
Th2 cytokines among its direct transcriptional targets, such
as the IL-5 and IL-13 promoters, whose activity is critically
dependent on GATA-3 binding (49-51). In the case of IL-4,
regulation by GATA-3 is not likely to be via direct
transactivation despite the identification of GATA-3 binding
sites around the IL-4 gene (52, 53). Deletion of GATA-3 in
well-differentiated Th2 cells results in a significant reduction
in the production of IL-5 and IL-13, whereas the expression
of IL-4 is unaffected (47), supporting this notion. Likewise
GATA-3 probably also serves as a chromatin remodeling
factor rather than a direct transactivator of the IL-10 gene
(54), another Th2 cytokine. GATA-3 is sufficient to induce
permissive epigenetic modifications in the IL-10 locus in an
IL-4-independent manner but dose not directly transactivate
the IL-10 promoter. Similar to IL-4, the expression of IL-10
is independent of GATA-3 in well-differentiated Th2 cells
(S.Y.P. and I.C.H., unpublished data).
The epigenetic modification of the IL-4, IL-5, and IL-13
loci, present within a 200 kb Th2 locus and controlled by a
highly conserved locus control region (LCR) within the
Rad50 gene located between the IL-5 and IL-13 genes (55),
on chromosome 11 has been extensively reviewed (56, 57).
Various epigenetic modifications, including methylation,
acetylation, and phosphorylation of histones and methylation/
demethylation of CpG islands of DNA, impose “permissive”
or “repressive” changes on the Th2 locus via several
cis-acting regulatory regions that are conserved in sequence
through evolution. Permissive modifications permit, whereas
repressive modifications deny, the access of transcriptional
machinery to the promoters of the Th2 cytokine genes. The
critical role of epigenetic modifications in shaping the
phenotype of Th cells has more recently been elucidated by
studies using Th cells rendered deficient in either Dnmt1, a
DNA methyltrasferase, or Mbd2, a methyl-CpG-binding
protein (58, 59). Both Dnmt1 and Mbd2 enhance methylation
of DNA and facilitate the formation of a repressive
conformation. Th cells deficient in either Dnmt1 or Mbd2
aberrantly produce a high level of IL-4 even under Th1
It is believed that GATA-3 plays a critical role in the
establishment of a full permissive conformation of the Th2
locus (35, 51, 60). But how GATA-3 accomplishes this is
poorly understood. The C-terminal finger of GATA-1 can
interact with CREB-binding protein, CBP, which contains
histone acetyltransferase activity (61). A recent study further
suggests that GATA-3, T-bet, CBP/p300, HDAC-3, and
HDAC-5 may form a high order protein complex (62). But
how the formation of this high order complex, which
contains nuclear proteins that have opposite effect on the
chromatin conformation, influences the epigenetic modification
of the Th2 locus in Th cells is unclear. Finally, several recent
18 GATA-3 – Not Just for Th2 Cells Anymore
Volume 4 Number 1 February 2007
studies have revealed that GATA-3 and Stat6 binding are
associated with complex long-range intrachromosomal
interactions that generate loops of DNA in the Th2 locus and
physically juxtapose the promoters of the cytokine genes (63,
64). The formation of densely packed loops of DNA in
activated Th2 cells requires the induction of a “genomic
organizer” SATB1 (special AT-rich sequence binding protein
1), which binds to nine base unpairing regions (BURs) within
the Th2 locus. Four of the nine BURs are located in the LCR.
SATB1 then folds the locus into densely packed loops by
anchoring the locus to scaffold proteins. Other proteins
including c-maf, also a Th2 cell-specific transcription factor
that is a potent transactivator of the IL-4 gene (65, 66), RNA
polymerase II and Brg1, a chromatin-remodeling ATPase
subunit of BAF complex also are recruited to the looped Th2
locus in activated Th cells. These intriguing data portray the
temporal sequence of the molecular events leading to stable
and coordinated expression of Th2 cytokines. But the role of
GATA-3 in maintaining the permissive conformation of the
Th2 locus once established is probably limited. “Quasi-Th2”
cells were generated by introducing a “deletable” GATA-3
gene into differentiating Th1 cells (67). These Th2 cells
expressed type 2 cytokines and had undergone permissive
epigenetic modifications in the Th2 locus. Deletion of the
exogenous GATA-3 gene in these Th2 cells, however, only
had a subtle impact on the epigenetic modifications of the
GATA-3 and control of thymocyte differentiation
GATA-3 is not only preferentially expressed in the Th2
lineage and critical for Th2 differentiation and function, but
also exhibits regulated expression throughout thymic
development. The following section reviews critical studies
using knock-in, transgenic, RNAi and conditional knockout
approaches demonstrating that GATA-3 is required at both
the β-selection step and CD4/CD8 differentiation step of
Normal expression pattern and the effects of overexpression
Thymic development is traditionally described by the pattern
of cell surface markers expressed at each stage (Figure 1). T
progenitors that seed the thymus initially express neither
CD4 nor CD8 and are termed double-negative (DN), which
in turn are divided into DN1, DN2, DN3, and DN4 stages
based on their expression of CD44 and CD25. After
expression and triggering of the pre-TCR, composed of the
invariant pre-T α chain and the TCRβ chain, DN3 thymocytes
undergo so-called β-selection, a checkpoint that ensures that
only those cells which have rearranged the TCRβ gene
successfully are allowed to divide and differentiate. DN4
cells then undergo proliferation and differentiate into cells
expressing both CD4 and CD8, termed double positive (DP).
DP cells rearrange the TCRα gene, and expression of mature
CD8SPCD8SPTreg TregCD4SP CD4SP
Figure 1. Schematic diagram of the development of T cell lineage. ETP stands for early thymic progenitor. The dark arrows indicate
Cellular & Molecular Immunology 19
Volume 4 Number 1 February 2007
α/β TCR leads to the process of positive and negative
selection, ensuring a diverse repertoire of T cells with
appropriate avidity and specificity. CD4hiCD8hiDP thymo-
cytes that have undergone positive selection upregulate
markers such as CD69 and downregulate CD8 slightly
(Figure 2). These CD4hiCD8intCD69hi positively selected
cells contain committed CD4 and CD8 progenitors (68, 69).
These committed progenitors then undergo a binary lineage
decision step and differentiate into CD4 single positive
(CD4SP) and CD8 single positive (CD8SP) cells, which have
fully downregulated the opposite co-receptor and then are
exported to the periphery.
The expression of GATA-3 during the development of
thymocytes has been characterized using a lacZ gene inserted
into the GATA-3 locus as a reporter (70). A low to moderate
level of expression of lacZ can be detected in every stage of
thymic development and its expression is further induced
during the transition from the DN3 to the DN4 stage and
from the DP to CD4SP stage. These two waves of induction
correspond nicely with β-selection and positive selection,
when engagement of antigen receptors with selective
antigens takes place. Indeed, expression of GATA-3 is
induced in DP thymocytes by signals derived from TCR (71).
CD4SP thymocytes and peripheral CD4+ T cells maintain a
high level of GATA-3, whereas the expression of GATA-3 is
quickly downregulated once DP cells mature into CD8SP
thymocytes and peripheral CD8+ T cells.
Several strains of mice expressing transgenic GATA-3
specifically in T cells during thymic development have been
generated. One transgenic line, in which a GATA-3 transgene
is driven by a CD2 promoter, displays impaired maturation of
CD8SP cells and consequently has a reduced number of
peripheral CD8+ T cells (72). Surprisingly, approximately 50%
of these mice spontaneously develop thymomas composed of
CD4+CD8loCD3+ cells. These results, although interesting,
have not been reproduced in other GATA-3 transgenic lines,
which have otherwise unremarkable thymic development (31,
38). The number and subset distribution of thymocytes in
these lines are very comparable to those of wild type mice
despite the apparent overexpression of GATA-3. The
overexpression approach thus suggests that endogenous
GATA-3 is probably already expressed at a saturating level in
thymocytes of later stages.
GATA-3 is indispensable for the development of CD4SP
The molecular mechanism of how the CD4/CD8 lineage
decision is made has been recently reviewed (73-75). Over
the past few years, the landscape of our understanding of the
transcriptional regulation of CD4/CD8 development has
changed from that of a blank slate thanks to definitive studies
demonstrating the indispensable roles of Th-POK (also
known as c-krox) and GATA-3 in CD4SP development.
The transcriptional control of CD4/CD8 lineage
determination was previously elusive, though there was
reason to suspect that the processes of positive selection,
commitment to the CD4 lineage and post-commitment
CD4SP survival were separable. Temporally, the testing of
randomly generated α/β TCR for the appropriate range of
specificity and avidity through positive and negative
selection occurs simultaneously with the downregulation of
one coreceptor, thereby matching of CD4 expression with
MHC class II (MHC-II) restriction and CD8 expression with
MHC class I (MHC-I) restriction. That the helper-deficient or
so-called HD mutant mouse (76) exhibited a selective lack of
CD4SP thymocytes while generating positively selected
CD8SP thymocytes demonstrated that positive selection and
lineage determination were functionally separable. Indeed,
when these mice were crossed to the MHC-II restricted AND
TCR transgenic mice, in which all positive selecting
thymocytes are expected to become CD4SP cells, transgenic
T cells were nevertheless driven into the CD8SP lineage,
indicating that the HD gene was required for CD4SP lineage
determination (77). Positional cloning of the HD gene
revealed a spontaneous A to G change at nucleotide position
1165 resulting in Arg to Gly substitution within the second
zinc finger of a transcription factor which the group named
T-helper-inducing POZ/Kruppel-like factor or Th-POK (78).
This gene was previously known as c-Krox, is induced in
positively selected thymocytes and is preferentially expressed
in CD4SP but not in CD8SP thymocytes (78, 79). Forced
expression of Th-POK in thymocytes destined to become
CD8SP cells was sufficient to drive thymocytes into the
CD4SP lineage (78, 79). Thus, Th-POK is essential and
sufficient for the development of CD4SP thymocytes and is
the only factor shown to control lineage determination,
independently of MHC restriction.
The role of GATA-3 in CD4SP development,
demonstrated by gene deletion and RNA interference
approaches, was unexpected, and GATA-3 appears to control
not lineage commitment but post-commitment CD4SP
survival. Conditional GATA-3-deficient mice were generated
using the Cre-lox system to further study the role of GATA-3
during intrathymic T cell development. Mice deficient in
GATA-3 at the DN4 stage, henceforth called G3-CD4Cre
mice, were created by deleting the GATA-3 gene with a Cre
recombinase driven by the CD4 promoter. These mice had a
drastic and selective reduction in the number of CD4SP
subset (80). In contrast, total thymocyte numbers and the
number and maturation of DP and CD8SP thymocytes were
apparently normal even though the GATA-3 gene was also
deleted in these cells. This result is similar but not identical
to what was
observed when the expression of GATA-3 was suppressed
using RNA interference in reaggregate fetal thymic organ
culture (71). In this in vitro system, the development of
CD4SP thymocytes was also attenuated but there was a
reciprocal increase in the percentage and number of CD8SP
subset. This discrepancy most likely originates from
differences between in vitro fetal thymic organ culture and in
vivo thymocyte development in adult animals.
Although G3-CD4Cre mice have almost no mature
CD4SP thymocytes, a substantial number of mature CD4SP
thymocytes can actually be found in G3-lckCre mice, and as
described above, exhibit defective Th2 differentiation. This
discrepancy is not due to incomplete deletion of GATA-3 by
20 GATA-3 – Not Just for Th2 Cells Anymore
Volume 4 Number 1 February 2007
the lckCre transgene because the mature CD4SP population
found in the G3-lckCre mice have undergone Cre-mediated
deletion of the GATA-3 gene, contain only residual GATA-3
protein, and express a slightly reduced level of TCR, a
feature of GATA-3 deficient T cells. It is still unclear how the
CD4SP thymocytes found in G3-lckCre mice can develop in
the absence of GATA-3. One possible scenario is that
thymocytes, once they survive β-selection in the absence of
GATA-3, become less dependent on GATA-3 in subsequent
developmental stages. Alternatively, the kinetics of GATA-3
gene deletion in the G3-lckCre mice and half-life of
previously translated protein could allow GATA-3 to persist
just long enough to allow CD4SP maturation to occur.
The virtual absence of CD4SP thymocytes could indicate
that GATA-3 is essential for the commitment of DP to
CD4SP lineage. According to this scenario, all positively
selected DP cells, including those destined to become CD4SP
cells, would be channeled into CD8SP cells in the absence of
GATA-3, such as in the HD mouse. An alternative scenario is
that GATA-3 is required for the survival or final
differentiation of CD4SP cells after commitment. These two
scenarios can be distinguished by introducing an MHC-II
restricted TCR transgene into GATA-3-deficient mice. If
GATA-3 is required for CD4 lineage commitment,
transgene-expressing DP thymocytes will be converted into
CD8SP cells. In contrast, a lack of transgene-expressing
CD4SP and CD8SP cells will argue for a defect at a
post-commitment stage. When the DO11.10 or AND TCR
transgene (S.Y.P. and I.C.H., unpublished data) was
introduced into GATA-3-deficient mice, there was still a
marked reduction in the number of CD4SP cells and no
conversion of transgene-expressing DP cells into CD8SP
cells (80), a result in agreement with the latter scenario.
The mechanism by which GATA-3 controls CD4SP
survival has not been characterized, though potential avenues
of exploration are suggested by two other gene-deficient
mouse models, CD83 deficient and c-myb deficient mice,
which have similar phenotypes. CD83 is an immunoglobulin-
like transmembrane protein expressed mainly in APC and
thymic epithelium (81). CD83-deficient mice also have a
striking reduction in CD4SP population but a normal number
of CD8SP cells (82). Similar to what was observed in
GATA-3-deficiency, the AND TCR transgene failed to rescue
the differentiation of CD4SP cells or give rise to AND-
or CD83L (?)
Figure 2. Two models of the generation of single positive thymocytes. CD83L stands for CD83 ligand.
Cellular & Molecular Immunology 21
Volume 4 Number 1 February 2007
positive CD8SP cells. The defect appears to reside in thymic
radio-resistant cells because CD83-deficient thymus was
unable to support the differentiation of AND-bearing wild
type CD4SP thymocytes in mixed chimeric hosts. It is
proposed that thymocytes express an ill-identified ligand for
CD83 and that the interaction between CD83 on thymic
stromal cells and CD83L on differentiating thymocytes is
indispensable for the differentiation of CD4SP cells. This
intriguing result suggests that GATA-3 and CD83L pathway
may intersect at the post-commitment stage.
The thymic phenotypes of GATA-3 deficiency also
resemble those of c-myb-deficient mice. Germline deficiency
of c-myb resulted in a complete and early block of thymocyte
development (83). Descendants of c-myb-deficient ES cells
could still be detected in the thymi of chimeric hosts in a
RAG-2 complementation system, a result different from what
was observed with GATA-3-deficient ES cells. These c-myb-
deficient thymocytes are CD44loCD25-, carry unrearranged
TCRβ loci, and may represent very early thymic progenitors,
a stage even more immature than the classical DN1 cells.
When the c-myb gene was deleted at an early DN stage
through the Cre-lox system, a profound block at β-selection
was also observed, which was similar to G3-lckCre mice as
detailed in a later section (84, 85). This block is most likely
caused by a defect in Dβ-Jβ and Vβ-DβJβ recombination
rather than in post-transcriptional expression of the TCRβ
gene as seen in GATA-3-deficient DN3 cells. Interestingly,
the c-myb-deficient mice also have a significant reduction in
the number of CD4SP thymocytes but the number of CD8SP
thymocytes is nearly normal. Introduction of an MHC-II-
restricted TCR transgene not only failed to rescue the
development of CD4SP cells but also did not convert the
transgene-positive cells into the CD8SP subset, suggesting a
One emerging model is that GATA-3 and c-myb may act
in concert to regulate the same molecular events, or act in
sequential steps of the same pathways at several stages of
thymic development. Such functional interaction between
c-myb and GATA proteins has been demonstrated during the
differentiation of erythrocytes (86, 87). At the post-
commitment stage, GATA-3 (and c-myb) may regulate the
expression of the elusive CD83L or alternatively CD83L
signaling may be essential for maintaining the expression of
GATA-3. In contrast, Th-POK and GATA-3 clearly act in two
independent steps. Th-POK
determination of the CD4 lineage, which requires GATA-3
for subsequent differentiation or survival (Figure 2).
Critical roles of GATA-3 in invariant NKT cell development,
maturation, and function
Invariant NKT (iNKT) cells are a unique subset of T cells
expressing Vα14Jα18 (mouse) or Vα24Jα18 (human) T cell
receptors, which are often coupled with Vβ8, Vβ7, or Vβ2.
iNKT originate from thymic DP cells but, unlike
conventional α/β T cells, iNKT cells are positively selected
in the thymus by CD1d molecules expressed on the surface
of DP thymocytes. iNKT cells that have successfully
undergone positive selection further differentiate into either
dictates the lineage
CD4+ or CD4-CD8- mature iNKT cells and emigrate to
peripheral lymphoid organs. iNKT cells only make up
approximately 5% of peripheral T cells but they are capable
of rapidly, within hours, producing large amounts of various
cytokines, including IFN-γ, IL-4, and IL-13, upon
encountering antigens, a phenomenon called cytokine storm.
The natural antigens for iNKT cells are still being discovered
but thus far α-galactosylceramide (α-GC), a glycolipid
derived from marine sponge, is the most potent agonist for
iNKT cells. In addition to mounting cytokine storm, iNKT
cells also express many NK receptors and are capable of
killing tumor cells. A large body of evidence has
demonstrated that iNKT cells play important immunomodu-
latory roles in infection, autoimmunity, allergy, and tumor
immunity. Readers should refer to several recent reviews for
details of iNKT cell biology (88, 89). Recent studies indicate
that GATA-3 plays a crucial role in regulating the
development, maturation, and function of this unique subset
of T cells.
GATA-3 is also expressed in iNKT cells (90-92). Until
recently, very little was known about the role of GATA-3 in
regulating the development and function of iNKT cells. The
generation of conditional GATA-3-deficient mice has made it
possible to address this question. G3-CD4cre mice have a
near normal number of thymic iNKT cells but, surprisingly,
more than 90% of the iNKT cells are CD4-CD8- iNKT (93).
This is in sharp contrast to control mice, in which the ratio
between CD4+ and CD4-CD8- subsets of iNKT cells is
approximately 1:1. Most of the GATA-3-deficient iNKT cells
undergo apoptosis during the transition from the thymus to
peripheral lymphoid organs, resulting in a 6-fold reduction in
the number of iNKT cells in the spleen and a virtual absence
of iNKT cells in the liver. In contrast to thymic iNKT cells
that are CD69low, peripheral iNKT cells of adult mice express
a high level of CD69, a feature of activated T cells. But
peripheral iNKT cells of young mice are actually CD69low.
The transition from CD69low to CD69high takes place at two to
three weeks after birth. This peripheral maturation step is
apparently impaired in the absence of GATA-3 because
residual GATA-3-deficient iNKT cells fail to upregulate
CD69 once emigrate to peripheral lymphoid organs. More
importantly, GATA-3-deficient iNKT cells are impotent in
mounting a cytokine storm, produce neither IFN-γ nor type 2
cytokines, and fail to upregulate activation markers, such as
CD69 and CD40L, in response to intravenous α-GC. The
failure to mount a cytokine storm is mainly due to a defect in
TCR signal transduction. This signaling defect probably
occurs temporally upstream of protein kinase C and calcium
influx because GATA-3-deficient iNKT cells are still capable
of producing IFN-γ and upregulating the expression of CD69
normally in response to PMA/ionomycin stimulation. Despite
the normal production of IFN-γ, PMA/ionomycin-stimulated
GATA-3-deficient iNKT cells still fail to produce IL-4 or
IL-13, a result reflecting the cardinal function of GATA-3,
i.e., promoting the expression of type 2 cytokines. It is worth
pointing out though that GATA-3’s role in mediating TCR
signal transduction is probably unique to iNKT cells.
Deficiency of GATA-3 has little impact on the TCR signaling
22 GATA-3 – Not Just for Th2 Cells Anymore
Volume 4 Number 1 February 2007
of DP thymocytes or peripheral Th cells (46, 80). GATA-3-
deficient peripheral Th cells in fact already exhibit features
of activated/memory Th cells ex vivo. These observations
highlight the versatility of GATA-3, the function of which
can vary significantly depending on the needs of cells. In
agreement with this notion, GATA-3 has been shown to be
required for optimal production of both IFN-γ and type 2
cytokines by NK cells (94). Future investigation into how
GATA-3 modulates TCR signal transduction and whether
GATA-3 is required for cytotoxicity will greatly advance our
understanding of the molecular events regulating the function
of iNKT cells.
GATA-3 is needed for optimal β-selection
When the GATA-3 gene was deleted at DN2/DN3 stage, but
prior to β-selection, by a Cre recombinase driven by the
proximal lck promoter, there was a striking reduction in
thymic cellularity due to a partial block in the transition from
the DN3 to DN4 stage (80). The DN3 to DN4 transition is
dependent on successful β-selection, which requires fruitful
rearrangement and expression of TCRβ chain to couple with
pTCRα. The level of intracellular TCRβ chain was indeed
significantly diminished in GATA-3-deficient DN3 cells.
Such a result is consistent with the notion that GATA-3
serves as a transactivator of TCR genes by binding to their
enhancers. However, the TCRβ loci in GATA-3-deficient
DN3 cells, like those in wild type cells, had undergone
rearrangement and the level of TCRβ transcripts was
comparable between wild type and GATA-3-deficient DN3
cells. These results suggest that GATA-3 actually regulates
the expression of TCRβ at a post-transcriptional rather than
transcriptional step. Although impaired expression of TCRβ
may well explain the block in β-selection, GATA-3 probably
has additional roles in regulating the DN3 to DN4 transition.
When the DO11.10 TCR transgene was used to substitute for
a lack of pTCR, the block in DN3 to DN4 transition was still
observed in the absence of GATA-3, despite equivalent
transgene expression in wild type and GATA-3-deficient cells.
One possible explanation for this finding is that GATA-3 also
controls signaling events downstream of pTCR in DN3 cells.
This scenario remains to be validated.
GATA-3 and T progenitor commitment
GATA-3 expression during lymphoid development is
considered a canonical sign of early T commitment and has
long been known to be essential for this process. Anti-sense
oligonucleotides of GATA-3
differentiation of T cells from fetal liver progenitors in a fetal
thymic organ culture system (95). When GATA-3-deficient
lymphoid cells were reconstituted in a RAG blastocyst
complementation system, it was discovered that GATA-3-
deficient ES cells failed to contribute to the thymocyte
compartment in the chimeric mice. No GATA-3-deficient DN
thymocytes, the most immature stage of thymic ontogeny,
were detected in the chimeric mice, whereas the capacity to
reconstituting B cell compartment was comparable between
GATA-3-deficient and wild type ES cells (70, 96). These
strongly inhibited the
observations suggest that germline deletion of GATA-3 leads
to an early and complete block of T cell development.
However, the details of this block remain to be investigated.
It is possible that deficiency of GATA-3 either prevents early
T cell progenitors from seeding the thymus or blocks the
differentiation of early thymic progenitors from lymphoid
precursors. Not only is GATA-3 essential for the develop-
ment of T cells, the level and timing of expression of
GATA-3 are also critical for the fate of T cell lineage.
Overexpression of GATA-3 either in T cell progenitors or
early DN thymocytes actually hinders, rather than promotes,
the development of T cells partly by interfering with the
expression of the RAG genes (97-99). These surprising
results indicate that the timing and the level of expression of
GATA-3 have to be tightly regulated during the development
of T cells. Given the limitations of overexpression
approaches, answers to the exact function of GATA-3 during
early T commitment must await studies using conditionally
deficient or other models of GATA-3 deficiency.
Targets of GATA-3 in the thymus
Unlike mature T cells where some transcriptional targets of
GATA-3 have been defined, direct transcriptional targets in
the thymus have been elusive. Of note, some of the genes
previously regarded as target genes of GATA-3, including
CD8α (100) and TCR (11, 13), are normally expressed in
GATA-3 deficient thymocytes (80). Indeed, while the level of
TCR in the remaining CD8 T cells is slightly reduced, the
rearrangement and repertoire of the TCR are intact. With
regards to the TCRα locus, a conserved sequence block in
the Jα locus and the TCRα enhancer have been demonstrated
to bind GATA-3 in chromatin immunoprecipitation (101),
though the functional significance of this binding is not
known. Direct targets of GATA-3 in mature thymocytes,
DN3 cells or in T progenitors are thus poorly characterized
and are the subject of ongoing investigation.
As GATA-3 participates in nearly every stage of T cell
development, its activity has to be tightly regulated. Recent
studies have indicated that this can be achieved by
controlling the transcription of the GATA-3 gene,
degradation and post-translational modification of the
GATA-3 protein, and interactions with other nuclear proteins.
Numerous soluble factors, surface molecules, intracellular
signaling pathways, and transcription factors have been
shown to modulate the expression of GATA-3 in Th cells.
Most of the studies, however, fail to demonstrate a direct
effect on the transcription of the GATA-3 gene partly because
that the transcriptional regulation of the GATA-3 gene in T
cells is poorly understood. Below, we will discuss the recent
progress in the post-translation modifications of GATA-3 and
its interacting partners in the context of T cell biology.
GATA-3 interacting proteins
GATA-3 has been shown to interact with several nuclear
Cellular & Molecular Immunology 23
Volume 4 Number 1 February 2007
proteins, including ROG, FOG, Smad3, PU.1, and T-bet, that
are expressed in Th cells.
ROG is a zinc finger protein containing three C2H2-type
fingers in its C-terminus. The expression of ROG is rapidly
induced in response to TCR stimulation (102). Over-
expression of ROG suppresses the function of GATA-3 in
several in vitro and in vivo settings, probably by sequestering
GATA-3 from DNA (62, 71, 103). The level of ROG is
significantly higher in CD8+ T cells than in Th cells and ROG,
along with histone deacetylases, can bind to a ROG response
element located in the exon 4 of the IL-13 gene in a type 2
cytotoxic T cell-specific manner (104). It was therefore
proposed that the differential expression of ROG might partly
explain why CD8+ T cells are poor IL-4 producers. However,
ROG-deficient Th cells, although hyper-responsive to
anti-CD3 stimulation, can differentiate normally into Th1 and
Th2 cells and deficiency of ROG has no impact on the
susceptibility to EAE, a Th1 cell-mediated demyelinating
disease (105). Moreover, the production of IL-4 by
ROG-deficient CD8+ T cells is very comparable to that of
wild type CD8+ T cells. These observations suggest possible
functional redundancy between ROG and ROG-like proteins.
FOG is a multi-zinc finger protein and was originally cloned
as a GATA-1 interacting protein (106). It plays a critical but
complicated role in the development of erythroid/
megakaryocytic lineage by modulating the function of
GATA-1 (107). It was subsequently discovered that FOG
interacts with the N-terminal finger of GATA proteins (106,
108). Interestingly, FOG is expressed in naïve Th cells but is
downregulated in both Th1 and Th2 cells (109, 110). Forced
expression of FOG suppressed GATA-3-dependent dif-
ferentiation of Th2 cells but had a negligible effect on fully
differentiated Th2 cells, suggesting that FOG may serve as a
repressor of GATA-3 during the differentiation of Th cells.
Surprisingly, FOG-deficient Th2 cells, instead of over-
producing Th2 cytokines, actually express a somewhat lower
level of IL-4 than FOG heterozygous Th2 cells, implying that
normally FOG acts as a co-factor for GATA-3. Thus the
physiologic role of FOG in Th2 development is unclear.
FOG deficiency affects thymocyte development but does
not completely phenocopy GATA-3 deficiency. As deficiency
of FOG causes embryonic lethality (111), FOG-deficient T
cells were generated through RAG-2 complementation (109).
The authors reported a profound block during β-selection,
indistinguishable from that of the RAG-2 deficient host, and
were not able to determine at which stage of DN
development FOG deficient cells were blocked. While a
β-selection defect is consistent with what is seen in
G3-lckCre mice, the profundity of the block and the fact that
CD4 T cells were recovered in the periphery of these mice
indicate that FOG at best may act as a cofactor for GATA-3
at the T progenitor or DN thymocyte developmental stages.
GATA-3 interacts with Smad3, but not other Smad proteins,
and recruits Smad3 to the IL-5 promoter independently of
Smad3 binding to DNA (112). Such GATA-3/Smad3
interaction enhances the activity of GATA-3 and provides a
molecular explanation for the positive effect of TGF-β on the
production type 2 cytokines when administered at miniscule
doses. At a higher concentration of TGF-β that is close to the
physiological level, TGF-β actually interferes with the
differentiation of Th2 cells by inhibiting the expression of
GATA-3 (113, 114). The biological significance of the
GATA-3/Smad3 interaction therefore remains uncertain.
PU.1 is a member of the ETS family of transcription factor
and is essential for myeloid and lymphoid development (115).
Somewhat unexpectedly, the expression of PU.1, albeit at a
low level, was also detected in Th2 cells but not in Th1 cells,
and is restricted to low cytokine-secreting subset of Th2 cells
that produce a high level of CCL22 (116). Forced expression
of PU.1 suppressed cytokine production by Th2 cells,
whereas introduction of PU.1 siRNA had an opposite effect.
PU.1 physically interacted with GATA-3 and excluded it
from DNA. In IL-4high and CCL22low Th2 cells that express
little PU.1, GATA-3 was found to bind to a 3’ enhancer of the
IL-4 gene. The binding of GATA-3 to this enhancer was
prohibited in PU.1-expressing Th2 cells. The expression of
PU.1 therefore defines a subset of Th2 cells, but the in vivo
function of this subset of Th2 cells has yet to be investigated.
The latest addition to the list of GATA-3 interactors is T-bet,
the master regulator of Th1 cells. It was first reported that
GATA-4 or GATA-5 physically interacted with T-box
transcription factors, such as Tbx5 and Tbx20, and
synergistically transactivated several cardiac specific genes
(117, 118). It was subsequently discovered that T-bet could
interact with GATA-3 in thymocytes (119). The interaction is
dependent on the phosphorylation of T-bet at the tyrosine
residue 525 by ITK and inhibits the binding of GATA-3 to its
target DNA. Consequently, forced expression of wild type
T-bet but not an Y525F mutant inhibited the production of
type 2 cytokines in Th2 cells. This observation nevertheless
is difficult to reconcile with the finding that ITK-deficient Th
cells tend to differentiate into Th1 cells under non-polarizing
conditions (120, 121). It was recently reported that GATA-3
could interfere with the transactivation of the promoter of
fucosyltransferase VII by T-bet (62). Thus, the functional
consequence of T-bet/GATA-3 interactions can be bi-
directional, allowing these two opposing transcription factors
to counteract each other. Such a counteracting mechanism
may be operating at least in cells, such as thymocytes, newly
activated but undifferentiated Th cells, or iNK cells, in which
both factors co-exist.
Post-translational modifications of GATA-3
Differential expression of GATA-3 is critical to its function
and must be modulated precisely. This is partly achieved by
post-translational modification of GATA-3 protein. GATA-3
24 GATA-3 – Not Just for Th2 Cells Anymore
Volume 4 Number 1 February 2007
is a phosphoprotein and can be phosphorylated in Th2 cells
by p38 kinase in response to c-AMP (122). Treatment of Th2
cells with a specific inhibitor of p38 attenuated GATA-3-
dependent promoter activities and suppressed the c-AMP-
induced expression of IL-5 and IL-13. The p38-dependent
phosphorylation of GATA-3 may partly explain the
synergistic effect between c-AMP and exogenous GATA-3 in
converting Th1 cells into type 2 cytokine-producing cells
(60). Despite these intriguing observations, the putative
c-AMP-induced phosphorylation sites have yet to be
identified. GATA-3 has been shown to be a substrate of
protein kinase A (PKA), which phosphorylates the serine
residue of the KRRLSA sequence in between the two zinc
fingers of GATA-3 in breast cancer cells (123). However,
such PKA-mediated phosphorylation of GATA-3 has yet to
be demonstrated in T cells. GATA-3 is also constitutively
acetylated in T cells and the status of acetylation is not
altered by stimulation with a mitogen. Coincidentally, the
lysine of the KRRLSA sequence is the dominant acetylation
site of GATA-3 (45). Conversion of the KRR to AAA, as in
the KRR mutant of GATA-3, results in local hypoacetylation
and the KRR mutant can function as a dominant negative
mutant of GATA-3 in some assays. This observation is
consistent with a recent report showing mutation of a key
acetylation site of GATA-1 interferes with its in vivo
chromatin occupancy but not nuclear localization or protein
stability (124). Nevertheless, the mechanism of action of the
KRR mutant is still unclear. The mutation attenuates the
transcriptional activity but does not appear to affect the
expression, nuclear localization, capacity of remodeling the
Th2 locus, and DNA binding of GATA-3 (43).
More recently, it was shown that GATA-3 was
ubiquitinated and degraded by proteasomes. The ubi-
quitination of GATA-3 is dependent on the polycomb protein
Bmi-1 and the E3 ligase Mdm2 (125, 126). Both Bmi-1 and
Mdm2 can physically interact with GATA-3, resulting in
poly-ubiquitination and degradation of GATA-3. Over-
expression of Bmi-1 in Th cells differentiating under non-
polarizing conditions inhibited the expression of IL-4 but
reciprocally enhanced the production of IFN-γ. In contrast,
deficiency of Bmi-1 or suppression of Mdm2 expression has
an opposite effect on the differentiation of Th2 cells. This
ubiquitination-proteasome degradation pathway of GATA-3
can be counteracted by the TCR-activated Ras-ERK MAPK
cascade (126). This observation provides an attractive
explanation for the need of TCR signals, in addition to
IL-4/Stat6, for the induction of GATA-3 during the
differentiation of Th2 cells. Most of the studies of post-
translation modification of GATA-3 have been conducted in
in vitro systems and in the setting of Th cell differentiation.
The functional significance of these post-translational
modifications of GATA-3 in in vivo Th immune response or
in the development of thymocytes remains poorly
Structural and functional analyses of GATA-3
The non-conserved N-terminal half of GATA-3 contains two
activation domains and is followed by two zinc fingers that
are highly homologous to those of other GATA proteins.
Studies of GATA-1 and various mutants of GATA-3 from
patients with HDR syndrome have demonstrated that the
C-terminal zinc finger is required for DNA binding (127).
The N-terminal zinc finger is used for interaction with other
nuclear proteins and stabilizing the interactions between
DNA and the C-terminal zinc finger. The roles of these
functional domains of GATA-3 in the differentiation and
function of Th cells have been carefully examined by
introducing various mutants of GATA-3 into differentiating
Th cells in vitro. Deletion of the C-terminal zinc finger or
both transactivation domains rendered GATA-3 unable to
support the differentiation and function of Th2 cells (128,
129). The inhibitory effect of GATA-3 on the differentiation
of Th1 cells was also completely abrogated. Surprisingly, a
low level of remodeling of the Th2 locus, particularly at the
IL-13 gene, was still induced by these mutants. Most recently,
a novel conserved sequence YxKxHxxxRP located immediately
downstream of the C-terminal zinc finger was shown to be
essential for DNA binding, supporting the differentiation of
Th2 cells, inhibiting IFN-γ production, and remodeling of the
Th2 locus (130). Computer simulation studies indicate that
this novel sequence, particularly the basic residues and the
histidine, stabilizes interactions between GATA-3 and DNA.
The YxKxHxxxRP sequence is not deleted in the
aforementioned GATA-3 mutant that lacks the C-terminal
zinc finger, suggesting that both the C-terminal zinc finger
and the YxKxHxxxRP sequence are required for stable
interaction between GATA-3 and DNA. Deletion of the
N-terminal zinc finger also substantially hampered the
production Th2 cytokines, particularly IL-5, but had little
impact on the GATA-3’s ability to induce chromatin
remodeling or suppress the expression of IFN-γ (60, 129).
Although some of the data are still controversial, these
observations indicate that the functional “tasks” of GATA-3
during the differentiation of Th cells are not always
inter-dependent and that the mechanism of action of GATA-3
varies depending on the nature of the tasks.
GATA-3 is the only GATA member that is expressed in
Th cells. The exclusive expression of GATA-3 in Th cells
raises the question whether the critical roles of GATA-3 in T
cells can be replaced by other GATA proteins. Mast cells
express GATA-1 and GATA-2 but no GATA-3 and are
capable of producing a high level of type 2 cytokines upon
activation (131, 132). Ectopic expression of GATA-1,
GATA-2, GATA-3, or GATA-4 in differentiating Th1 cells all
suppressed the expression of IFN-γ and enhanced the
production of IL-4 and IL-5 (128). These studies suggest that
the role of GATA-3 can be substituted with other GATA
proteins. Nevertheless, GATA-4 appears to be less potent
than the three hematopoietic GATA proteins in supporting the
production of IL-4 and IL-5, a finding in agreement with a
few studies showing that not all GATA proteins are
functionally interchangeable. Germline deletion of GATA-1
causes a lethal defect in erythropoiesis during embryogenesis.
Expression of GATA-1 or GATA-2 under the transcription
control of GATA-1 is sufficient to rescue GATA-1-deficient
fetuses. Surprisingly, GATA-3 or GATA-4 expressed in the
Cellular & Molecular Immunology 25
Volume 4 Number 1 February 2007
same or similar manner is unable to rescue GATA-1-deficient
fetuses from embryonic lethality (133, 134). Taken together,
these observations argue for the presence of intrinsic
functional differences at least between GATA-4 and the
hematopoietic GATA proteins. The YxKxHxxxRP sequence
is conserved in all GATA proteins and cannot explain the
differences. Careful structural and functional analyses
comparing GATA-3 and the non-hematopoietic GATA
proteins, such as GATA-4, in physiological settings should
greatly advance our understanding of the mechanism of
action of GATA-3.
The functional role of GATA-3 in the biology of T cells has
expanded dramatically since the identification and cloning of
this versatile transcription factor. A great deal of knowledge
regarding the functional consequences of GATA-3 over-
expression and deficiency has been accumulated. However,
we are still in an early stage of understanding the mechanism
of action of GATA-3. Current data clearly indicate that the
mechanism of action of GATA-3 goes above and beyond
DNA binding and transactivation. Through its interactions
with DNA and various nuclear proteins, GATA-3 participates
in almost every stage of T cell development. But very little is
known as to how these interactions, with either DNA or
nuclear proteins, are coordinated and connected with chromatin-
remodeling machinery. Detailed structural and functional
analyses in combination with crystallography should help
address these important questions.
In addition, the genuine target genes of GATA-3, other
than the Th2 cytokine genes, still remain elusive.
Comparison of target genes in other tissues may prove to be
helpful here. GATA-3 not only is required at critical binary
lineage decision points such as the T vs B, CD4 vs CD8, and
Th1 vs Th2 branchpoints, in the immune system, but also was
recently shown to control survival of the mammary luminal
epithelial lineage in the breast (135). GATA-3 is also required
for normal development of skin, adipocytes, and nervous
system in mouse (136-138). It is tempting to speculate that
there are common themes of control across tissues, and that
GATA-3 acts by orchestrating the carefully timed expression
of lineage specific targets as well as proliferative or survival
programs. Identifying the GATA-3 target genes that are
essential for the generation of CD4SP thymocytes in
particular is expected to uncover novel approaches to
manipulating the function of the thymus. Such approaches
will lead to new treatments to boost the number of CD4+ T
cells, a condition that is desirable in numerous clinical
situations, such as congenital immunodeficiency, chemo-
therapy induced immunosuppression, bone marrow trans-
plantation and HIV infection.
This work is supported by an R01 grant from NIH (I.C.H.)
and a Child Health Research Grant from Charles H. Hood
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