The inositol 5-phosphatase SHIP-1 and adaptors Dok-1 and 2 play central roles in CD4-mediated inhibitory signaling

Immunol Lett. 2012 Mar 30;143(1):122-30. doi: 10.1016/j.imlet.2012.02.009. Epub 2012 Feb 24.

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.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / immunology*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Line
  • DNA-Binding Proteins / immunology*
  • DNA-Binding Proteins / metabolism
  • Inositol Polyphosphate 5-Phosphatases
  • Mice
  • Mice, Knockout
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
  • Phosphoproteins / immunology*
  • Phosphoproteins / metabolism
  • Phosphoric Monoester Hydrolases / deficiency
  • Phosphoric Monoester Hydrolases / immunology*
  • Phosphoric Monoester Hydrolases / metabolism
  • Phosphorylation
  • RNA-Binding Proteins / immunology*
  • RNA-Binding Proteins / metabolism
  • Receptors, Antigen, T-Cell / immunology
  • Signal Transduction*

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • Dok1 protein, mouse
  • Dok2 protein, mouse
  • Phosphoproteins
  • RNA-Binding Proteins
  • Receptors, Antigen, T-Cell
  • Phosphoric Monoester Hydrolases
  • Inositol Polyphosphate 5-Phosphatases
  • INPP5D protein, human
  • Inpp5d protein, mouse
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases