RESEARCH Open Access
PDLIM2 restricts Th1 and Th17 differentiation and
prevents autoimmune disease
Zhaoxia Qu1,2, Jing Fu1,2, Huihui Ma1,3, Jingjiao Zhou1,2, Meihua Jin1,2, Markus Y Mapara1,3, Michael J Grusby4
and Gutian Xiao1,2*
Background: PDLIM2 is essential for the termination of the inflammatory transcription factors NF-κB and STAT but
is dispensable for the development of immune cells and immune tissues/organs. Currently, it remains unknown
whether and how PDLIM2 is involved in physiologic and pathogenic processes.
Results: Here we report that naive PDLIM2 deficient CD4+T cells were prone to differentiate into Th1 and Th17
cells. PDLIM2 deficiency, however, had no obvious effect on lineage commitment towards Th2 or Treg cells.
Notably, PDLIM2 deficient mice exhibited increased susceptibility to experimental autoimmune encephalitis (EAE), a
Th1 and/or Th17 cell-mediated inflammatory disease model of multiple sclerosis (MS). Mechanistic studies further
indicate that PDLIM2 was required for restricting expression of Th1 and Th17 cytokines, which was in accordance
with the role of PDLIM2 in the termination of NF-κB and STAT activation.
Conclusion: These findings suggest that PDLIM2 is a key modulator of T-cell-mediated immune responses that
may be targeted for the therapy of human autoimmune diseases.
CD4+T helper (Th) cells play a central role in orchestrat-
ing immune responses to diverse microbial pathogens .
Upon activation by antigens, naive CD4+Tcells differenti-
ate into specialized effector T (Teff) cells (Th1, Th2, or
Th17), which secrete different patterns of cytokines and
perform different functions . Th1 cells produce inter-
feron-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) and
initiate cellular immune responses against intracellular
pathogens. Th2 cells generate interleukin-4 (IL-4), IL-5
and IL-13 and promote humoral responses against extra-
cellular parasites. Th17 cells make IL-17, IL-21 and IL-22
and confer immunity against extracellular bacteria and
fungi. Moreover, activated CD4+T cells also differentiate
into regulatory T (Treg) cells, which express transforming
growth factor-β (TGF-β), IL-10 and IL-35 and suppress
the functions of Teff cells, thereby keeping immune
responses in check.
Imbalance of Th cell differentiation and subsequent cyto-
kine dysregulation is implicated in inflammatory and
autoimmune diseases . In particular, Th1 and Th17 cells
and their signature cytokines IFN-γ and IL-17 have been
shown to play a critical role in the development of autoim-
mune responses in many autoimmune diseases, including
multiple sclerosis (MS) and rheumatoid arthritis [2-4]. In
accordance with the significance of Th cell differentiation
in animal physiology and pathology, the molecular mechan-
isms underlying this important process have been exten-
sively investigated. In this regard, the signal transducers and
activators of transcription (STAT) proteins are well known
for their essential roles in transmitting cytokine-mediated
signals and specifying Th cell differentiation [1,2]. In gen-
eral, STAT4 is activated mainly by IL-12 and type I IFNs,
and it functions predominantly in promoting Th1 cell dif-
ferentiation. STAT6 is activated in response to IL-4 and
functions as the molecular switch for initiation of the Th2
cell differentiation program. Soon after activation by IL-6,
STAT3 triggers Th17 commitment. On the other hand, IL-
2-activated STAT5 facilitates Treg cell differentiation. Simi-
lar to STAT proteins, the NF-κB transcription factors, par-
ticularly the prototypical member RelA (also known as
p65), are also master regulators/activators of immune
responses and inflammation in both healthy and disease
[5,6]. The signaling pathways leading to activation of STAT
* Correspondence: email@example.com
1University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
2Department of Microbiology and Molecular Genetics, Pittsburgh, PA, USA
Full list of author information is available at the end of the article
Cell & Bioscience
© 2012 Qu et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Qu et al. Cell & Bioscience 2012, 2:23
and NF-κB proteins have been well demonstrated [7,8].
However, it still remains largely unknown how activated
STAT and NF-κB are terminated for proper Th cell differ-
entiation and immune responses and how STAT and NF-
κB are deregulated in autoimmune diseases.
Previous studies show that PDLIM2, a ubiquitously
expressed PDZ-LIM domain-containing protein with
high expression in lymphoid tissues and cells including
T lymphocytes, is required for the termination of STAT
and NF-κB activation [9,10]. More recent studies suggest
that PDLIM2 may function as a tumor suppressor
[11-15]. Mechanistic studies indicate that PDLIM2 se-
lectively promotes ubiquitination and proteasomal deg-
radation of nuclear (activated) STAT4 and RelA proteins
[9-12]. However, whether and how PDLIM2 is involved
in Th cell differentiation remain unknown. In particular,
mouse genetic studies reveal that PDLIM2 is not
required for the development of immune cells and im-
mune tissues/organs . Additionally, it remains un-
known whether PDLIM2 is involved in the pathogenesis
of inflammatory and autoimmune diseases.
Results and discussion
PDLIM2 deficiency in CD4+th cells enhances Th1 and
Th17 cell differentiation but has no obvious effect on Th2
and Treg cell differentiation
To test whether PDLIM2 is involved in Th cell differenti-
ation, naive CD4+Th cells were isolated from spleens of
PDLIM2−/−and PDLIM2+/+mice and stimulated by anti-
CD3/anti-CD28 under Th1, Th2, Th17 or Treg polarizing
condition. Loss of PDLIM2 did not affect the differentiation
of Th cells to Th2 or Treg, as evidenced by similar numbers
of Th2 and Treg cells produced from naive PDLIM2−/−and
PDLIM2+/+CD4+Th cells (Figure 1). In contrast, much
more Th1 and Th17 cells were generated from naive
PDLIM2−/−CD4+Th cells compared to PDLIM2+/+cells.
These data suggest that PDLIM2 plays a specific role in
restricting Th1 and Th17 cell differentiation.
Mice deficient in PDLIM2 show increased susceptibility to
Given the causative role of Th1 and Th17 cells in auto-
immune diseases such as MS [2-4], we proposed that
through restriction of Th1 and Th17 cell differentiation,
PDLIM2 is involved in autoimmune disease suppression.
To test this hypothesis and to further characterize the
in vivo role of PDLIM2 in regulating Th1 and Th17 cell
differentiation, we examined
PDLIM2−/−and PDLIM2+/+mice to EAE, a well-defined
model of MS . In agreement with previous studies
, 20% of PDLIM2+/+mice developed acute EAE with a
2.8 mean peak clinical score and a mean disease onset of
day 17.3±2.5) of post-immunization with the encephalito-
genic PLP180-199epitope (Figure 2). Remarkably, over 50%
of PDLIM2−/−mice developed EAE with an earlier disease
onset (13.1±1.9 day of post-immunization) and a more
Figure 1 Enhanced Th1 and Th17 differentiation of PDLIM2 deficient CD4+Th cells. Naive CD4+Th cells isolated from PDLIM2+/+(WT) or
PDLIM2−/−(KO) mice were stimulated for 72 hours with anti-CD3/anti-CD28 under Th1, Th2, Th17 or Treg polarizing condition, followed by
intracellular cytokine staining and flow cytometry. The data are representative of at least three independent experiments with similar results.
Qu et al. Cell & Bioscience 2012, 2:23
Page 2 of 7
severe (3.7 mean peak clinical score) and prolonged dis-
ease course. These data clearly indicate that PDLIM2 plays
a critical role in suppressing EAE.
PDLIM2 expression in CD4+T cells is critical for EAE
To determine whether the effect of PDLIM2 deficiency
on EAE is CD4+T-cell specific, we performed adoptive
T-cell transfer studies using SCID mice as
receipts, which lack CD4+T cells. Although the disease
severity in adoptive transfer recipients was less robust
overall than that observed in immunized mice, the dif-
ference of EAE induction in the receipts of PDLIM2+/+
versus PDLIM2−/−T cells was still significant and similar
to that observed in PDLIM2+/+and PDLIM2−/−mice
(Figure 3). These data suggest that the observed increase
in EAE severity in PDLIM2−/−mice is due to the defi-
ciency of PDLIM2 in CD4+T cells.
PDLIM2 deficiency leads to increased STAT and NF-κB
activation and augmented production of Th1 and Th17
As EAE is mediated by Th1 and/or Th17 cells , we
examined whether the exacerbated EAE in PDLIM2−/−
mice is associated with increased Th1 and Th17 cell dif-
ferentiation in the mice. As expected, the expression
levels of Th1 cytokines (IFN-γ and TNF-α) and Th17
cytokines (IL-17, IL-21 and IL-22) were significantly
higher in PLP180-199-stimulated PDLIM2−/−mice com-
pared to the PDLIM2+/+mice under the same treatment
(Figure 4A). On the other hand, the expression levels of
Th2 cytokines (IL-4, IL-5 and IL-13) and Treg cytokines
(TGF-β and IL-10) were comparable in the PLP180-199-
treated PDLIM2+/+or PDLIM2−/−mice. These data
Figure 2 Increased susceptibility to EAE in PDLIM2 deficient mice. A) Incidence, B) disease progression, C) severity and D) onset of EAE in
PDLIM2+/+and PDLIM2−/−mice (n=15). Mice were immunized with PLP180–199peptide and monitored daily for EAE disease symptoms. The p
values between the PDLIM2+/+(WT) and PDLIM2−/−(KO) groups are at least smaller than 0.05 by two tailed t-test.
Figure 3 Increased severity of adoptive transfer EAE in
recipients of PDLIM2 deficient CD4+T cells. CD4+T cells were
isolated from PDLIM2+/+and PDLIM2−/−mice immunized with
PLP180–199peptide and transferred i.v. into SCID recipients (n=20).
One day after the cell transfer, recipient mice also received an
injection of pertussis. Mice were then monitored for the symptoms
of EAE as described in Figure 2.
Qu et al. Cell & Bioscience 2012, 2:23
Page 3 of 7
suggest that PDLIM2 suppresses EAE through limiting
Th1 and Th17 cell differentiation.
To determine the molecular mechanisms by which
PDLIM2 controls Th1 and Th17 cell differentiation for
EAE suppression, we examined the expression levels of
STAT4 and RelA proteins in the nucleus (activation
marker) of CD4+T cells isolated from PLP180-199-treated
PDLIM2+/+mice or PDLIM2−/−mice. In this regard, it is
known that PDLIM2 promotes proteasomal degradation
of nuclear STAT4 and RelA proteins [9-12]. More im-
portantly, STAT4 is a determinative factor of Th1 cell
differentiation and also participates in Th17 cell differ-
entiation [18,19]. On the other hand, RelA regulates
transcriptional expression of numerous cytokines that
are involved in Th1 and Th17 cell differentiation and
EAE pathogenesis such as IFNs, TNF-α and IL-6 . In
fact, a recent study has already linked RelA to Th17 re-
sponse . Given the critical role of STAT3 in Th17
cell differentiation , we also included STAT3 in our
studies. As shown in Figure 4B, significantly higher levels
of STAT3, STAT4 and RelA proteins were detected in
PLP180-199-treated T cells from PDLIM2−/−mice as com-
pared to those from PDLIM2+/+mice. The increased nu-
clear expression/activation of STAT3, STAT4 and RelA
should be the driving force but not the consequences of
enhanced Th1 and Th17 cell differentiation nor the out-
come of exacerbated EAE in PDLIM2−/−mice, because an
obvious increase in the nuclear expression of STAT3,
STAT4 and RelA proteins was already detected within 30
minutes after cell stimulation (Figure 4C). Our biochem-
ical studies indicated that similar to its role in the negative
regulation of STAT4 and RelA (9–12), PDLIM2 bound to
nuclear STAT3 for ubiquitination and proteasomal deg-
radation (Figure 5). During the preparation of our manu-
script, another group also showed that PDLIM2 targets
STAT3 for degradation . These data together suggest
that PDLIM2 negatively regulates activation of STAT3/4
and RelA and therefore restricts Th1 and Th17 cell differ-
entiation and prevents EAE development.
The STAT and NF-κB transcription factors play critical
roles at multiple levels of the immune system in both
health and disease, including the autoimmune inflamma-
tory response [1-6]. The mechanisms of how STAT and
NF-κB are activated to drive immune responses have
been well defined [7,8]. However, how those key immune
regulators are negatively regulated during Th cell differ-
entiation and how they become constitutively and per-
sistently activated in autoimmune diseases remain
largely unknown. The data presented in this study de-
monstrate that PDLIM2 functions as an essential
Figure 4 Enhanced nuclear expression of STAT3/4 and RelA proteins and augmented production of Th1 and Th17 cytokines in PDLIM2
deficient Teff cells. Splenic T cells from day 10 PLP180–199-immunized PDLIM2+/+(WT) or PDLIM2−/−(KO) mice were subjected to QRT-PCR to
detect the relative expression levels of the indicated cytokines genes (A) or ELISA to detect the nuclear expression levels of STAT3, STAT4 and
RelA (B). The expression levels of the indicated genes and proteins were represented as fold induction relative to their WT controls. C) Naive
PDLIM2−/−or PDLIM2+/+CD4+Th cells were stimulated for the indicated time points with anti-CD3/anti-CD28 under Th1 or Th17 polarizing
condition, followed by ELISA to detect the nuclear expression levels of STAT3 (in response to Th17 stimulation), STAT4 and RelA (in response to
Th1 stimulation). In A-C, n=3, *, p<0.03; **, p<0.003 by two tailed t-test.
Qu et al. Cell & Bioscience 2012, 2:23
Page 4 of 7
modulator of Th1 and Th17 cell differentiation but has
no apparent effect on Th2 and Treg cell differentiation.
Interestingly, the novel function of PDLIM2 in Th cell
differentiation is most likely through restricting activa-
tion of STAT3/4 and RelA. These data identify STAT3
as a new target of PDLIM2 for ubiquitin-mediated pro-
teasomal degradation and also suggest a new mechanism
of RelA in immune responses involving regulation of
Th1 and Th17 cell differentiation. These findings pro-
vide important insights into molecular mechanisms
underlying immune responses and suggest PDLIM2 as
a new therapeutic target for inflammatory and auto-
PDLIM2−/−mice were backcrossed with BALB/c mice at
least 10 generations for pure BALB/c background.
BALB/c mice were housed under specific pathogen-free
conditions at the Hillman Cancer Center of the Univer-
sity of Pittsburgh Cancer Institute. Animal experiments
were approved by the Institutional Animal Care and Use
Committee (IACUC) of the University of Pittsburgh.
Experimental autoimmune encephalitis (EAE) induction
and clinical scoring
Six to eight-week-old female mice were immunized sub-
cutaneously with PLP180–199 peptide (200 μg/mouse,
Genemed Synthesis Inc.) emulsified in CFA containing
Mycobacterium tuberculosis H37Ra (500 μg/mouse, BD
Diagnostics). Mice also received 300 ng of pertussis
toxin (List Biological Laboratories) intraperitoneally (i.p.)
at the time of immunization and 48 hours later. Mice
were monitored daily for clinical signs of paralysis and
scored as follows: 0, no clinical signs; 1, limp tail; 2,
weak/partially paralyzed hind legs; 3, limp tail and
complete paralysis of hind legs; 4, complete hind and
partial front leg paralysis; 5, complete paralysis or mori-
Adoptive transfer of CD4+T cells for induction of EAE
Lymph nodes and spleens were harvested from PDLIM2+/+
or PDLIM2−/−mice immunized with PLP180–199, and
lymph node cells and splenocytes were cultured in vitro
Figure 5 Ubiquitination and proteasomal degradation of STAT3 by PDLIM2. A) Physical interaction between PDLIM2 and STAT3. Nuclear
extracts of 293 cells transfected with HA-STAT3 alone or together with Myc-PDLIM2 were subjected to immunoprecipitation (IP) using Myc
antibody and immunoblotting (IB) using HA antibody. The expression levels of HA-STAT3 and Myc-PDLIM2 were examined by IB. B) Polyubiquitination
of STAT3 by PDLIM2. 293 cells were transfected with HA-STAT3 plus Flag-ubiquitin in the presence or absence of Myc-PDLIM2, followed by nuclear
fractionation. The nuclear extracts were subjected to IP using HA antibody and IB using Flag antibody. The expression levels of HA-STAT3 and
Myc-PDLIM2 were examined by IB. C) Proteasomal degradation of STAT3 by PDLIM2. 293 cells transfected with HA-STAT3 alone or together with
Myc-PDLIM2 were cycloheximide (CHX)-chased for the indicated time, followed by nuclear extractions and IB using HA or Myc antibody. In lanes 3 and
6, the cells were chased in the presence of 10 μM MG132.
Qu et al. Cell & Bioscience 2012, 2:23
Page 5 of 7
with 1 μM PLP180–199and IL-2 for 72 h. CD4+Tcells were
then positively selected by MACS separation using mag-
netic CD4+microbeads (Miltenyi Biotec, Auburn, CA) per
manufacturer’s instructions. 5 x 106CD4+T cells were
adoptively transferred by intravenous (i.v.) injection into
SCID recipients on day 0. On day 2, mice received an i.p.
injection of pertussis toxin (250 ng), and mice were then
monitored for symptoms of disease.
CD4+th cell purification and in vitro differentiation
Naive CD4+CD25-T cells were first isolated from spleno-
cytes using CD4+T-cell Isolation Kit (Miltenyi Biotec.) and
then sorted out by FACSAria (BD Biosciences). Purified
naive CD4+CD25-Tcells were stimulated with plate-bound
anti-CD3 and anti-CD28 (1 μg/ml) under Th1 (mIL-2
10 ng/ml, mIL-12 10 ng/ml), Th2 (IL-4 10 ng/ml, anti-
IFNγ 10 μg/ml), Th17 (anti-IFNγ 10 μg/ml, anti-IL-4
10 μg/ml, hIL-6 10 ng/ml, hTGF-β 10 ng/ml) or Treg
(hTGFβ, 10 ng/ml, anti-IL-4 10 μg/ml, anti-IFNγ 10 μg/ml)
(BD Biosciences or eBioscience) polarizing condition. 72
hours after the initial stimulation, the cells were subjected
to intracellular cytokine staining (ICS)/flow cytometry ana-
lysis and quantitative real-time RT-PCR (QRT-PCR) as
ICS and flow cytometry
T cells were stimulated for 5 hours with PMA (50 ng/ml)
and ionomycin (500 ng/ml) in the presence of intracellular
transport inhibitor monesin (10 μg/ml; Sigma), followed
by fixation with paraformaldehyde (2%) and permeabliza-
tion with saponin (0.5%). Cells were then treated with
anti-IFN-γ-FITC (XMG1.2), anti-IL-4-PE (11B11), anti-
IL-17-PE (TC11-18 H10), and anti-Foxp3–FITC (FJK-
16 s) (BD Biosciences or eBioscience). Data were acquired
using FACSCalibur (BD Biosciences) and analyzed using
CellQuest software (Becton Dickinson) as described previ-
Total RNA was prepared with TRIZOL reagent and
cDNA was generated with SuperScript II reverse tran-
scriptase (Invitrogen), followed by real-time PCR assays
using Fast start SYBR Green reagents (Roche) as des-
cribed [24,25]. The gene-specific primer pairs were:
IFN-γ, 5’-TTCTTCAGCAACAGCAAGGCGAA-3’ and
5’-TGAATGCTTGGCGCTGGACCTG-3’; TNF-α, 5’-G
ATGAGAAGTTCCCAAATGGC-3’ and 5’-ACTTGGT
GGTTTGCTACGACG-3’; TGF-β, 5’-TGACGTCACT
GGAGTTGTACGG-3’ and 5’-GGTTCATGTCATGGAT
GGTGC-3’; IL-4, 5’-AGGGACGCCATGCACGGAGAT-
3’ and 5’-GCGAAGCACCTTGGAAGCCCTAC-3’; IL-5,
5’-AGCACAGTGGTGAAAGAGACCTT-3’ and 5’-TCC
AATGCATAGCTGGTGATTT-3’; IL-10, 5’-AGCTGAA
GACCCTCAGGATGCG-3’ and 5’- TCATTCATGGCC
TTGTAGACACCTTG-3’; IL-13, 5’-GGCTCTTGCTTG
CCTTGGTG-3’ and 5’-TCCATACCATGCTGCCGTT
G-3’; IL-17, 5’-CTCAGACTACCTCAACCGTTC-3’ and
5’-TGAGCTTCCCAGATCACAGAG-3’; IL-21, 5’-ATCC
TGAACTTCTATCAGCTCCAC-3’ and 5’-GCATTTAG
CTATGTGCTTCTGTTTC-3’; IL-22, 5’-TCCGAGGAG
TCAGTGCTAAA-3’ and 5’-AGAACGTCTTCCAGGG
TGAA-3’; β-actin, 5′-ACCCGCGAGCACAGCTTCTT
TG-3’ and 5’-CTTTGCACATGCCGGAGCCGTTG-3’.
Expression levels of each gene were normalized to that
Enzyme-linked immunosorbent assay (ELISA)
Cell nuclear fractions were prepared and added to 96-well
plate precoated with anti-RelA, anti-STAT3 or anti-
STAT4. After overnight incubation at 4 °C, plates were
washed extensively with PBS containing 0.1% Tween 20
(PBST), and horseradish peroxidase-conjugated secondary
antibodies were added and incubated for 1 hour at room
temperature. After extensive wash with PBST, a colorimet-
ric substrate 2’2-azinobis(3-ethylenzthiazoline-6-sulfonic
acid) (ABTS) was added and incubated for 15 minutes.
The reaction was stopped by addition of 100 μL 1% so-
dium dodecyl sulfate (SDS). The optical density at 405 nm
(OD405) was measured with an automated plate spectro-
photometer (Thermo Lab Systems).
Immunoblotting (IB) and immunoprecipitation (IP) assays
Nuclear extracts were subjected to SDS-PAGE and IB,
or IP using the indicated antibodies before SDS-PAGE
and IB as described before [26,27].
In vivo ubiquitin conjugation assay
Cytoplasmic and nuclear extracts were prepared from
HTLV-I-transformed T cells or 293 cells transfected with
HA-STAT3 together with Flag-tagged ubiquitin in the
presence or absence of Myc-PDLIM2, immediately fol-
lowed by IP using anti-HA. The ubiquitin-conjugated
STAT3 pulled down by IP was detected by IB using anti-
Protein stability assay
Cells were treated with 10 μM CHX, followed by chase
of the indicated time period in the presence or absence
of MG132, and IB to detect the indicated proteins .
Data were reported as mean±standard deviation (SD).
The Student’st test (two tailed) was used to assess signifi-
cance of differences between two groups, and p values
≤0.05 and 0.01 were considered statistically significant
and highly statistically significant, respectively.
Qu et al. Cell & Bioscience 2012, 2:23
Page 6 of 7
Abbreviations Download full-text
ABTS: 2’2-azinobis(3-ethylenzthiazoline-6-sulfonic acid); EAE: Experimental
autoimmune encephalitis; ELISA: Enzyme-linked immunosorbent assay;
IB: Immunoblotting (IB); ICS: Intracellular cytokine staining; IFN-γ: Interferon-γ;
IL: Interleukin; IP: Immunoprecipitation; (i.p.): Intraperitoneal; (i.v.): Intravenous;
MS: Multiple sclerosis; QRT-PCR: Quantitative reverse transcription-
polymerase chain reaction; PDLIM2: PDZ-LIM domain-containing protein 2;
STAT: Signal transducers and activators of transcription; SDS: Sodium dodecyl
sulfate; TGF-β: Transforming growth factor-β; Th: T helper; Teff: Effector T;
TNF-α: Tumor necrosis factor-α.
The authors declare that they have no competing interests.
ZQ, JF, HM, JZ and MJ performed experiments; MM analyzed data and
criticized the paper; MG contributed vital new reagents and criticized the
paper; ZQ and GX designed the research, analyzed data and wrote the
paper. All authors read and approved the final manuscript.
The authors thank J.A. Lyons for critical technical assistance. This study was
supported in part by the National Institute of Health (NIH)/National Cancer
Institute (NCI) grant R01 CA116616 and American Cancer Society (ACS)
Awards RSG-06-066-01-MGO (G. X.) and PF-12-081-01-TBG (Z. Q.). M.Y.M and
H.M were supported in part by NHLBI grant RO1 HL093716 and
RO1GM063569. This project also used the UPCI shared co-facilities supported
in part by the NIH/NCI grant P30CA047904.
1University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.2Department
of Microbiology and Molecular Genetics, Pittsburgh, PA, USA.3Department of
Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
4Department of Immunology and Infectious Diseases, Harvard School of
Public Health, Boston, MA, USA.
Received: 21 March 2012 Accepted: 6 June 2012
Published: 25 June 2012
1. O'Shea JJ, Paul WE: Mechanisms underlying lineage commitment and
plasticity of helper CD4+ T cells. Science 2010, 327:1098–1102.
2.Jäger A, Kuchroo VK: Effector and regulatory T-cell subsets in autoimmunity
and tissue inflammation. Scand J Immunol 2010, 72:173–184.
3.Fletcher JM, Lalor SJ, Sweeney CM, Tubridy N, Mills KH: T cells in multiple
sclerosis and experimental autoimmune encephalomyelitis. Clin Exp
Immunol 2010, 162:1–11.
4. Toh ML, Miossec P: The role of T cells in rheumatoid arthritis: new
subsets and new targets. Curr Opin Rheumatol 2007, 19:284–288.
5.Xiao G, Rabson A, Young W, Qing G, Qu Z: Alternative pathways of NF-κB
activation: a double-edged sword in health and disease. Cytokine Growth
Factor Rev 2006, 17:281–293.
6. Brown KD, Claudio E, Siebenlist U: The roles of the classical and
alternative nuclear factor-κB pathways: potential implications for
autoimmunity and rheumatoid arthritis. Arthritis Res Ther 2008, 10:212.
7.Santos CI, Costa-Pereira AP: Signal transducers and activators of
transcription-from cytokine signaling to cancer biology. Biochim Biophys
Acta 2011, 1816:38–49.
8. Xiao G, Fu J: NF-κB and cancer: a paradigm of Yin-Yang. Am J Cancer Res
9.Tanaka T, Soriano MA, Grusby MJ: SLIM is a nuclear ubiquitin E3 ligase
that negatively regulates STAT signaling. Immunity 2005, 22:729–736.
10.Tanaka T, Grusby MJ, Kaisho T: PDLIM2-mediated termination of
transcription factor NF-κB activation by intranuclear sequestration and
degradation of the p65 subunit. Nat Immunol 2007, 8:584–591.
11.Qu Z, Fu J, Yan P, Hu J, Cheng S, Xiao G: Epigenetic repression of PDLIM2:
implications for the biology and treatment of breast cancer. J Biol Chem
12. Qu Z, Yan P, Fu J, Jiang J, Grusby MJ, Smithgall TE, Xiao G: DNA
methylation-dependent repression of PDLIM2 in colon cancer and its
role as a potential therapeutic target. Cancer Res 2010, 70:1766–1772.
13.Yan P, Fu J, Qu Z, Li S, Tanaka T, Grusby MJ, Xiao G: PDLIM2 suppresses
HTLV-I Tax-mediated tumorigenesis by targeting Tax into the nuclear
matrix for proteasomal degradation. Blood 2009, 113:4370–4380.
Yan P, Qu Z, Li S, Ishikawa C, Mori N, Xiao G: HTLV-I-mediated repression
of PDLIM2 involves DNA methylation but independent of the viral
oncoprotein Tax. Neoplasia 2009, 11:1036–1041.
Fu J, Yan P, Li S, Qu Z, Xiao G: Molecular determinants of PDLIM2 in
suppressing HTLV-I Tax-mediated tumorigenesis. Onocogene 2010,
Morel L: Mouse models of human autoimmune diseases: essential tools
that require the proper controls. PLoS Biol 2004, 2:E241.
Lyons JA, Ramsbottom MJ, Mikesell RJ, Cross AH: B cells limit epitope
spreading and reduce severity of EAE induced with PLP peptide in
BALB/c mice. J Autoimmun 2008, 31:149–155.
Nishikomori R, Usui T, Wu CY, Morinobu A, O'Shea JJ, Strober W: Activated
STAT4 has an essential role in Th1 differentiation and proliferation that
is independent of its role in the maintenance of IL-12R beta 2 chain
expression and signaling. J Immunol 2002, 169:4388–4398.
Mathur AN, Chang HC, Zisoulis DG, Stritesky GL, Yu Q, O'Malley JT, Kapur R,
Levy DE, Kansas GS, Kaplan MH: Stat3 and Stat4 direct development of
IL-17-secreting Th cells. J Immunol 2007, 178:4901–4907.
Ruan Q, Kameswaran V, Zhang Y, Zheng S, Sun J, Wang J, DeVirgiliis J, Liou HC,
Beg AA, Chen YH: The Th17 immune response is controlled by the Rel-
RORγ-RORγ T transcriptional axis. J Exp Med 2011, 208:2321–2333.
Harris TJ, Grosso JF, Yen HR, Xin H, Kortylewski M, Albesiano E, Hipkiss EL,
Getnet D, Goldberg MV, Maris CH, Housseau F, Yu H, Pardoll DM, Drake CG:
Cutting edge: an in vivo requirement for STAT3 signaling in TH17
development and TH17-dependent autoimmunity. J Immunol 2007,
Tanaka T, Yamamoto Y, Muromoto R, Ikeda O, Sekine Y, Grusby MJ, Kaisho T,
Matsuda T: PDLIM2 inhibits T helper 17 cell development and
granulomatous inflammation through degradation of STAT3. Sci Signal
Qu Z, Sun D, Young W: Lithium promotes neural precursor cell
proliferation: evidence for the involvement of the non-canonical GSK-3β-
NF-AT signaling. Cell Biosci 2011, 1:18.
Fu J, Qu Z, Yan P, Ishikawa C, Ageilan RI, Rabson AB, Xiao G: The tumor
suppressor gene WWOX links the canonical and noncanonical NF-κB
pathways in HTLV-I Tax-mediated tumorigenesis. Blood 2011,
Qing G, Qu Z, Xiao G: Endoproteolytic processing of C-terminally
truncated NF-κB2 precursors at κB-containing promoters. Proc Natl Acad
Sci U S A 2007, 104:5324–5329.
Qing G, Qu Z, Xiao G: Regulation of NF-κB2 p100 processing by its cis-
activating domain. J Biol Chem 2005, 280:18–27.
Qing G, Yan P, Xiao G: Hsp90 inhibition results in autophagy-mediated
proteasome-independent degradation of IκB kinase (IKK). Cell Res 2006,
Qu Z, Qing G, Rabson R, Xiao G: Tax deregulation of NF-κB2 p100
processing involves both β-TrCP-dependent and independent
mechanisms. J Biol Chem 2004, 279:44563–44572.
Qing G, Qu Z, Xiao G: Stabilization of basally translated NF-κB-inducing
kinase (NIK) protein functions as a molecular switch of processing of
NF-κB2 p100. J Biol Chem 2005, 280:40578–40582.
Cite this article as: Qu et al.: PDLIM2 restricts Th1 and Th17
differentiation and prevents autoimmune disease. Cell & Bioscience 2012
Qu et al. Cell & Bioscience 2012, 2:23
Page 7 of 7