The cytoplasmic domain of CD28 is both necessary and sufficient for costimulation of interleukin-2 secretion and association with phosphatidylinositol 3'-kinase.
T-cell activation requires two signaling events. One is provided by the engagement of the T-cell antigen receptor, and the second represents a costimulatory signal provided by antigen-presenting cells. CD28 mediates a costimulatory signal by binding its ligands, B7-1 and B7-2, on antigen-presenting cells, but the signaling pathway activated by CD28 ... has not been identified. A homologous molecule, CTLA-4, expressed on activated T cells, also binds to B7-1 and B7-2, but whether it has a signaling function is not known. We performed a structure-function analysis of CD28 to identify the functional domain which activates signal transduction. Truncation of the 40-amino-acid CD28 cytoplasmic tail abrogated costimulatory signaling. Chimeric constructs containing the extracellular and transmembrane regions of CD8 linked to the cytoplasmic region of CD28 had a costimulatory signaling function. Similar chimeras containing the cytoplasmic tail of CTLA-4 did not signal. Thus, the cytoplasmic region of CD28, but not CTLA-4, is sufficient to mediate costimulatory signaling. In addition, after CD28 stimulation, the p85 subunit of phosphatidylinositol 3'-kinase and phosphatidylinositol 3'-kinase activity were found in CD28 immunoprecipitates. The CD8-CD28 chimera, which has a costimulatory signaling function, associates with p85, while the nonfunctioning CD8-CTLA-4 chimera and a CD8-zeta chimera do not associate with p85. These results suggest that phosphatidylinositol 3'-kinase is specifically activated by CD28 and may mediate proximal events in the costimulatory signaling pathway regulated by CD28.
Mesh Terms:
Abatacept, Amino Acid Sequence, Antigens, CD, Antigens, Differentiation, CD28 Antigens, CTLA-4 Antigen, Cell Line, Cloning, Molecular, Cytoplasm, Humans, Immunoconjugates, Interleukin-2, Molecular Sequence Data, Phosphatidylinositol 3-Kinases, Phosphotransferases (Alcohol Group Acceptor), Polymerase Chain Reaction, Recombinant Fusion Proteins, Sequence Deletion, Sequence Homology, Amino Acid, Signal Transduction, T-Lymphocytes, Transfection, Tumor Cells, Cultured
Abatacept, Amino Acid Sequence, Antigens, CD, Antigens, Differentiation, CD28 Antigens, CTLA-4 Antigen, Cell Line, Cloning, Molecular, Cytoplasm, Humans, Immunoconjugates, Interleukin-2, Molecular Sequence Data, Phosphatidylinositol 3-Kinases, Phosphotransferases (Alcohol Group Acceptor), Polymerase Chain Reaction, Recombinant Fusion Proteins, Sequence Deletion, Sequence Homology, Amino Acid, Signal Transduction, T-Lymphocytes, Transfection, Tumor Cells, Cultured
Mol. Cell. Biol.
Date: May. 01, 1994
PubMed ID: 8164687
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