CTLA4-Ig modifies dendritic cells from mice with collagen-induced arthritis
to increase the CD4þCD25þFoxp3þ regulatory T cell population
q
Hyeok-Jae Ko
a
,
b
, Mi-La Cho
b
, Seon-Yeong Lee
b
, Hye-Jwa Oh
b
, Yu-Jung Heo
b
,
Young-Mee Moon
b
, Chang-Min Kang
b
, Seung-Ki Kwok
a
,
b
, Ji Hyeon Ju
a
,
b
,
Sung-Hwan Park
a
,
b
, Kyung-Su Park
a
,
b
,
**
, Ho-Youn Kim
a
,
b
,
*
a
Division of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, School of Medicine, Seoul, South Korea
b
Rheumatism Research Center, Catholic Institutes of Medical Science, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-040, South Korea
article info
Article history:
Received 15 April 2009
Received in revised form
4 July 2009
Accepted 20 July 2009
Keywords:
Collagen-induced arthritis
CTLA4-Ig
Dendritic cells
Regulatory T cells
TGF-
b
abstract
Cytotoxic T lymphocyte antigen-4 (CTLA4) and IgG fusion protein, CTLA4-Ig, is a therapeutic agent used
for rheumatoid arthritis. It binds B7 molecules on dendritic cells (DCs) and thereby blocks B7/CD28
costimulatory interaction and inhibits effective T cell proliferation. However, the effect of CTLA4-Ig on the
regulatory T cell (Treg) is still not known. In this study, we investigated the influence of CTLA4-Ig on the
CD4þCD25þFoxp3þ Treg population in collagen-induced arthritis (CIA) mouse model. CTLA4-Ig sup-
pressed CIA and increased the CD4þCD25þFoxp3þ Treg population in joint and spleen. When
CD11c þ DCs and CD4þT cells from CIA mice were cultured with anti-CD3, CTLA4-Ig increased the
CD4þCD25 þ Foxp3þ Treg population in a TGF-
b
-dependent manner. When CD11c þ DCs from CIA mice
were treated with CTLA4-Ig and adoptively transferred into CIA-induced mice, arthritis did not develop
in association with the increase in CD4þCD25þFoxp3þ Treg population. However, in CTLA4-Ig-untreated
DC-transferred CIA mice, arthritis developed and then rapidly progressed. Our study demonstrated that
CTLA4-Ig suppressed CIA by modifying DCs from CIA mice into tolerogenic DCs to increase the
CD4þCD25þFoxp3þ Treg population and this seems to be the new immune regulatory mechanism of
CTLA4-Ig.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Regulatory T cells (Tregs) play a critical role in controlling the
immune response and preventing autoimmune diseases [1].
CD4þCD25þ Treg is one type of the Tregs and forkhead box P3
(Foxp3) is its representative marker [2–6]. Several studies have
shown that T cell receptor (TCR) ligation, B7/CD28 costimulatory
interaction, IL-2, and TGF-
b
are necessary for the generation of the
CD4þCD25þ Treg [4,7–9].
Cytotoxic T lymphocyte antigen-4 (CTLA4) and IgG1 fusion
protein, CTLA4-Ig, has been used for the treatment of rheumatoid
arthritis (RA). It interrupts B7/CD28 costimulatory interaction
and inhibits effective T cell activation and proliferation [10,11].
However, the effect of CTLA4-Ig on the CD4þCD25þ Treg has not
been clearly defined yet. CTLA4 on CD4þCD25þ Tregs and CTLA4-Ig
bind to B7 molecules and modify DCs to express indoleamine
2,3-dioxygenase (IDO) [12–14], a tryptophan-catabolizing enzyme
which induces and activates CD4þCD25þ Tregs [12,15,16].
CTLA4-Ig was reported to convert naı
¨
ve CD4
þ
CD25
À
T cells into
CD4þCD25þ Tregs by an antigen presenting cell (APC)-dependent
mechanism [14]. These findings suggest that CTLA4-Ig is able to
increase the CD4þCD25þ Treg population. However, the B7/CD28
costimulatory interaction also plays an important role in the
generation of the CD4þCD25þ Tregs [17,18], which means that
CTLA4-Ig can inhibit CD4þCD25þ Treg generation by blocking the
B7/CD28 costimulatory interaction [19]. Accordingly, CTLA4-Ig may
have both positive and negative effect on the CD4þCD25þ Treg
population [20] and it is not clear whether CTLA4-Ig increases or
decreases CD4þCD25þ Treg population.
Abbreviations: CIA-induced mice, mice in which primary immunization was
finished and booster immunization was not done or less than a week has passed
after the booster immunization; CIA mice, mice in which primary and booster
immunization were finished and more than a week has passed after the booster
immunization.
q
Authorship note: Hyeok-Jae Ko and Mi-La Cho contributed equally to this work.
*
Corresponding author. Tel.: þ82 2 2258 7470; fax: þ82 2 599 4287.
**
Corresponding author. Tel.: þ82 2 2258 6012; fax: þ82 2 599 4287.
E-mail addresses: pkyungsu@catholic.ac.kr (K.-S. Park), ho0919@catholic.ac.kr
(H.-Y. Kim).
Contents lists available at ScienceDirect
Journal of Autoimmunity
journal homepage: www.elsevier.com/locate/jautimm
0896-8411/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jaut.2009.07.006
Journal of Autoimmunity 34 (2010) 111–120