CTLA4-Ig modiﬁes dendritic cells from mice with collagen-induced arthritis
to increase the CD4þCD25þFoxp3þ regulatory T cell population
, Mi-La Cho
, Seon-Yeong Lee
, Hye-Jwa Oh
, Yu-Jung Heo
, Chang-Min Kang
, Seung-Ki Kwok
, Ji Hyeon Ju
, Kyung-Su Park
, Ho-Youn Kim
Division of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, School of Medicine, Seoul, South Korea
Rheumatism Research Center, Catholic Institutes of Medical Science, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-040, South Korea
Received 15 April 2009
Received in revised form
4 July 2009
Accepted 20 July 2009
Regulatory T cells
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-
-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
Ó 2009 Elsevier Ltd. All rights reserved.
Regulatory T cells (Tregs) play a critical role in controlling the
immune response and preventing autoimmune diseases .
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-
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
T cells into
CD4þCD25þ Tregs by an antigen presenting cell (APC)-dependent
mechanism . 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 . Accordingly, CTLA4-Ig may
have both positive and negative effect on the CD4þCD25þ Treg
population  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
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: firstname.lastname@example.org (K.-S. Park), email@example.com
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Journal of Autoimmunity
journal homepage: www.elsevier.com/locate/jautimm
0896-8411/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
Journal of Autoimmunity 34 (2010) 111–120