title: The inositol 5-phosphatase SHIP-1 and adaptors Dok-1 and 2 play central roles in CD4-mediated inhibitory signaling.
abstract: CD4 functions to enhance the sensitivity of T cells to antigenic peptide/MHC class II. However, if aggregated in isolation, e.g. in the absence of T cell receptor (TCR), CD4 can transduce yet undefined signals that lead to T cell unresponsiveness to antigen and apoptosis. In Human Immunodeficiency Virus-1 (HIV-1) disease, CD4(+) T cell loss can result from gp120-induced CD4 signaling in uninfected cells. We show here that CD4 aggregation leads to Lck-dependent phosphorylation of the RasGAP adaptors Downstream of kinase-1/2 (Dok-1/2) and the inositol 5-phosphatase-1 (SHIP-1) and association of the two molecules. Studies using SHIP-1 shRNA, knockout mice and decoy inhibitors further indicate that CD4-mediated inhibition of TCR-mediated T cell activation is SHIP-1 and Dok-1/2 dependent, and involves SHIP-1 hydrolysis of Phosphatidylinositol 3,4,5-trisphosophate (PI(3,4,5)P3) needed for TCR signaling. Our studies provide evidence for a novel mechanism by which ill-timed CD4-mediated signals activated by ligands such as HIV-1 gp120 lead to disarmament of the immune system.
authors.affiliation: Integrated Department of Immunology, University of Colorado School of Medicine and National Jewish Health, Denver, CO 80206, United States.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Waterman
authors.forename: Susanne
authors.initials: S
authors.lastname: Marschner
authors.forename: Erin
authors.initials: E
authors.lastname: Brandl
authors.forename: John C
authors.initials: JC
authors.lastname: Cambier
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000276:immunology* / Q000378:metabolism; D000072181:Inositol Polyphosphate 5-Phosphatases; D051379:Mice; D018345:Mice, Knockout; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010750:Phosphoproteins / Q000276:immunology* / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D016601:RNA-Binding Proteins / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C489561:Dok1 protein, mouse; C498444:Dok2 protein, mouse; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D011948:Receptors, Antigen, T-Cell; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases