Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation.
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.
Yokosuka
Tadashi
T
Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan. yokosuka@rcai.riken.jp
Kobayashi
Wakana
W
Takamatsu
Masako
M
Sakata-Sogawa
Kumiko
K
Zeng
Hu
H
Hashimoto-Tane
Akiko
A
Yagita
Hideo
H
Tokunaga
Makio
M
Saito
Takashi
T
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D053468:CARD Signaling Adaptor Proteins / Q000502:physiology; D018106:CD28 Antigens / Q000502:physiology; D017252:CD3 Complex / Q000502:physiology; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D007108:Immune Tolerance; D007527:Isoenzymes / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D011493:Protein Kinase C / Q000502:physiology; D000074121:Protein Kinase C-theta; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology
D015703:Antigens, CD; D053468:CARD Signaling Adaptor Proteins; D018106:CD28 Antigens; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C496467:Card11 protein, mouse; C556707:Ctla4 protein, mouse; D007527:Isoenzymes; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta