Regulation of the small GTPase Rap1 and extracellular signal-regulated kinases by the costimulatory molecule CTLA-4

Mol Cell Biol. 2005 May;25(10):4117-28. doi: 10.1128/MCB.25.10.4117-4128.2005.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigen-Presenting Cells / cytology
  • Antigen-Presenting Cells / immunology
  • Antigens, CD
  • Antigens, Differentiation / metabolism*
  • CTLA-4 Antigen
  • Cell Adhesion
  • Cell Line
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism
  • Humans
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Transgenic
  • Proto-Oncogene Proteins p21(ras)
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Transgenes / genetics
  • rap1 GTP-Binding Proteins / metabolism*

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ctla4 protein, mouse
  • GTPase-Activating Proteins
  • Extracellular Signal-Regulated MAP Kinases
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • rap1 GTP-Binding Proteins