Regulation of the small GTPase Rap1 and extracellular signal-regulated kinases by the costimulatory molecule CTLA-4.
The mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) is activated following engagement of the T-cell receptor and is required for interleukin 2 (IL-2) production and T-cell proliferation. This activation is enhanced by stimulation of the coreceptor CD28 and inhibited by the coreceptor CTLA-4. We show that the small G protein Rap1 is regulated in the opposite manner; it is inhibited by CD28 and activated by CTLA-4. Together, CD3 and CTLA-4 activate Rap1 in a sustained manner. To delineate T-cell function in the absence of Rap1 activity, we generated transgenic mice expressing Rap1GAP1, a Rap1-specific GTPase-activating protein. Transgenic mice showed lymphadenopathy, and transgenic T cells displayed increased ERK activation, proliferation, and IL-2 production. More significantly, the inhibitory effect of CTLA-4 on T-cell function in Rap1GAP1-transgenic T cells was reduced. We demonstrate that CTLA-4 activates Rap1, and we propose that intracellular signals from CTLA-4 antagonize CD28, at least in part, at the level of Rap1.
Dillon
Tara J
TJ
Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239, USA.
Carey
Kendall D
KD
Wetzel
Scott A
SA
Parker
David C
DC
Stork
Philip J S
PJ
D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism*; D060908:CTLA-4 Antigen; D002448:Cell Adhesion; D002460:Cell Line; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016283:Proto-Oncogene Proteins p21(ras); D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D020690:GTPase-Activating Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D020827:rap1 GTP-Binding Proteins