Involvement of Rap-1 activation and early termination of immune synapse in CTLA-4-mediated negative signal.
Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a T cell co-stimulation receptor that delivers inhibitory signals upon activation. This inhibitory effect by CTLA-4 requires activation of small GTPase Rap-1. However, the precise mechanism underlying these negative signals remains unclear. Here, we show that CTLA-4-induced suppression of IL-2 production correlates with rapid destabilization of immunological synapse (IS) formation in murine normal T cell clones. Overexpression of Spa-1, a Rap-1-specific GTPase activating protein (GAP), abolished both Rap-1 activation and IL-2 suppression induced by CTLA-4. Although we failed to find any specific inhibition of activation of early signals upon CTLA-4 engagement, we found that CTLA-4 specifically up-regulates cell motility and suppresses prolonged accumulation of Talin at the contact area with antigen presenting cells upon antigen stimulation. These results suggest that Rap-1 is activated upon CTLA-4 ligation and mediates inhibitory signals through prevention of IS formation.
Hara
Satoru
S
Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehirocho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Nakaseko
Chiaki
C
Yamasaki
Sho
S
Hattori
Masakazu
M
Bos
Johannes L
JL
Saito
Yasushi
Y
Minato
Nagahiro
N
Saito
Takashi
T
D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D060908:CTLA-4 Antigen; D002460:Cell Line; D002465:Cell Movement; D004789:Enzyme Activation; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D054992:Immunological Synapses / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology; D051189:Murinae; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D016608:Talin / Q000032:analysis / Q000276:immunology; D015854:Up-Regulation; D020827:rap1 GTP-Binding Proteins / Q000819:agonists / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; D060908:CTLA-4 Antigen; D020690:GTPase-Activating Proteins; D007376:Interleukin-2; D016608:Talin; D020827:rap1 GTP-Binding Proteins