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

99 Citations (Scopus)

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 1 2010
Externally publishedYes

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T-Lymphocytes
Regulatory T-Lymphocytes
T-Cell Antigen Receptor
Protein Kinase C
Ligands
Proteins
In Vitro Techniques

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Yokosuka, T., Kobayashi, W., Takamatsu, M., Sakata-Sogawa, K., Zeng, H., Hashimoto-Tane, A., ... 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

Spatiotemporal Basis of CTLA-4 Costimulatory Molecule-Mediated Negative Regulation of T Cell Activation. / Yokosuka, Tadashi; Kobayashi, Wakana; Takamatsu, Masako; Sakata-Sogawa, Kumiko; Zeng, Hu; Hashimoto-Tane, Akiko; Yagita, Hideo; Tokunaga, Makio; Saito, Takashi.

In: Immunity, Vol. 33, No. 3, 01.09.2010, p. 326-339.

Research output: Contribution to journalArticle

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, vol. 33, no. 3, pp. 326-339. https://doi.org/10.1016/j.immuni.2010.09.006
Yokosuka T, Kobayashi W, Takamatsu M, Sakata-Sogawa K, Zeng H, Hashimoto-Tane A et al. Spatiotemporal Basis of CTLA-4 Costimulatory Molecule-Mediated Negative Regulation of T Cell Activation. Immunity. 2010 Sep 1;33(3):326-339. https://doi.org/10.1016/j.immuni.2010.09.006
Yokosuka, Tadashi ; Kobayashi, Wakana ; Takamatsu, Masako ; Sakata-Sogawa, Kumiko ; Zeng, Hu ; Hashimoto-Tane, Akiko ; Yagita, Hideo ; Tokunaga, Makio ; Saito, Takashi. / Spatiotemporal Basis of CTLA-4 Costimulatory Molecule-Mediated Negative Regulation of T Cell Activation. In: Immunity. 2010 ; Vol. 33, No. 3. pp. 326-339.
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