TY - JOUR
T1 - Spatiotemporal Basis of CTLA-4 Costimulatory Molecule-Mediated Negative Regulation of T Cell Activation
AU - Yokosuka, Tadashi
AU - Kobayashi, Wakana
AU - Takamatsu, Masako
AU - Sakata-Sogawa, Kumiko
AU - Zeng, Hu
AU - Hashimoto-Tane, Akiko
AU - Yagita, Hideo
AU - Tokunaga, Makio
AU - Saito, Takashi
N1 - Funding Information:
We thank S. Hori at RIKEN RCAI for discussions and H. Yamaguchi and S. Kato for secretarial assistance. This work was supported by a Grant-in-Aid for Priority Area Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (T.Y., K.S.S., M.T., and T.S.).
PY - 2010/9
Y1 - 2010/9
N2 - T cell activation is positively and negatively regulated by a pair of costimulatory receptors, CD28 and CTLA-4, respectively. Because these receptors share common ligands, CD80 and CD86, the expression and behavior of CTLA-4 is critical for T cell costimulation regulation. However, in vivo blocking of CD28-mediated costimulation by CTLA-4 and its mechanisms still remain elusive. Here, we demonstrate the dynamic behavior of CTLA-4 in its real-time competition with CD28 at the central-supramolecular activation cluster (cSMAC), resulting in the dislocalization of protein kinase C-θ and CARMA1 scaffolding protein. CTLA-4 translocation to the T cell receptor microclusters and the cSMAC is tightly regulated by its ectodomain size, and its accumulation at the cSMAC is required for its inhibitory function. The CTLA-4-mediated suppression was demonstrated by the in vitro anergy induction in regulatory T cells constitutively expressing CTLA-4. These results show the dynamic mechanism of CTLA-4-mediated T cell suppression at the cSMAC.
AB - T cell activation is positively and negatively regulated by a pair of costimulatory receptors, CD28 and CTLA-4, respectively. Because these receptors share common ligands, CD80 and CD86, the expression and behavior of CTLA-4 is critical for T cell costimulation regulation. However, in vivo blocking of CD28-mediated costimulation by CTLA-4 and its mechanisms still remain elusive. Here, we demonstrate the dynamic behavior of CTLA-4 in its real-time competition with CD28 at the central-supramolecular activation cluster (cSMAC), resulting in the dislocalization of protein kinase C-θ and CARMA1 scaffolding protein. CTLA-4 translocation to the T cell receptor microclusters and the cSMAC is tightly regulated by its ectodomain size, and its accumulation at the cSMAC is required for its inhibitory function. The CTLA-4-mediated suppression was demonstrated by the in vitro anergy induction in regulatory T cells constitutively expressing CTLA-4. These results show the dynamic mechanism of CTLA-4-mediated T cell suppression at the cSMAC.
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U2 - 10.1016/j.immuni.2010.09.006
DO - 10.1016/j.immuni.2010.09.006
M3 - Article
C2 - 20870175
AN - SCOPUS:77957099358
SN - 1074-7613
VL - 33
SP - 326
EP - 339
JO - Immunity
JF - Immunity
IS - 3
ER -