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research
ICOS regulates the generation and function of human CD4+ Treg in a CTLA-4 dependent manner
Authors
A Tuettenberg
AJ Currie
+58 more
AJ McAdam
AT Bauquet
BS Clay
C Conrad
C Dong
CE Rudd
CI Liakou
David B. Lewis
E Chuang
EM Bertram
G Galicia
Gang Qin
GS Whitehead
H Chen
H Harada
J Wu
J Zheng
JG Egen
Jian Zheng
K Uchida
K Wing
KC Beier
KI Mead
KM Smith
Kwok-Tai Lam
L Strauss
M Gigoux
M Gomez de Agüero
M Kornete
M Ono
M Watanabe
MA Linterman
ML Alegre
N Martin-Orozco
N Prevot
N Takahashi
Olaf Rotzschke
PA Taylor
PF Yong
Ping-Lung Chan
R Hodgson
S Maeda
S Read
T Ito
T Lischke
T Takahashi
TV Moore
W Tu
Wenwei Tu
Y Burmeister
Y Chen
Y Grinberg-Bleyer
Y Koguchi
Y Wu
Y Zheng
Yinping Liu
Yu-Lung Lau
Zheng Xiang
Publication date
1 January 2013
Publisher
'Public Library of Science (PLoS)'
Doi
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on
PubMed
Abstract
Inducible co-stimulator (ICOS) is a member of CD28/Cytotoxic T-lymphocyte Antigen-4 (CTLA-4) family and broadly expressed in activated CD4+ T cells and induced regulatory CD4+ T cells (CD4+ iTreg). ICOS-related signal pathway could be activated by the interaction between ICOS and its ligand (ICOSL). In our previous work, we established a cost-effective system to generate a novel human allo-antigen specific CD4hi Treg by co-culturing their naïve precursors with allogeneic CD40-activated B cells in vitro. Here we investigate the role of ICOS in the generation and function of CD4hi Treg by interrupting ICOS-ICOSL interaction with ICOS-Ig. It is found that blockade of ICOS-ICOSL interaction impairs the induction and expansion of CD4hi Treg induced by allogeneic CD40-activated B cells. More importantly, CD4hi Treg induced with the addition of ICOS-Ig exhibits decreased suppressive capacity on alloantigen-specific responses. Dysfunction of CD4hi Treg induced with ICOS-Ig is accompanied with its decreased exocytosis and surface CTLA-4 expression. Through inhibiting endocytosis with E64 and pepstatin A, surface CTLA-4 expression and suppressive functions of induced CD4hi Treg could be partly reversed. Conclusively, our results demonstrate the beneficial role of ICOS-ICOSL signal pathway in the generation and function of CD4hi Treg and uncover a novel relationship between ICOS and CTLA-4. © 2013 zheng et al.published_or_final_versio
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