Spatiotemporal Basis of CTLA-4 Costimulatory Molecule-Mediated Negative Regulation of T Cell Activation

Tadashi Yokosuka, Wakana Kobayashi, Masako Takamatsu, Kumiko Sakata-Sogawa, Hu Zeng, Akiko Hashimoto-Tane, Hideo Yagita, Makio Tokunaga, Takashi Saito

Research output: Contribution to journalArticle

104 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)326-339
Number of pages14
JournalImmunity
Volume33
Issue number3
DOIs
StatePublished - Sep 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Yokosuka, T., Kobayashi, W., Takamatsu, M., Sakata-Sogawa, K., Zeng, H., Hashimoto-Tane, A., Yagita, H., Tokunaga, M., & Saito, T. (2010). Spatiotemporal Basis of CTLA-4 Costimulatory Molecule-Mediated Negative Regulation of T Cell Activation. Immunity, 33(3), 326-339. https://doi.org/10.1016/j.immuni.2010.09.006