Defective CD4+ T cell signaling in murine AIDS: uncoupling of the T cell receptor complex from PIP2 hydrolysis.
CD4+ T cells from mice with murine AIDS (MAIDS) have been shown to be unable to respond to TCR stimulation as measured by proliferation, IL-2 production, or IL-2R upregulation, although responsiveness was restored with PMA and ionomycin. In this report we have demonstrated that the inability of MAIDS CD4+ T cells to respond to CD3 stimulation was not associated with reduced surface expression of CD3, CD4, or CD28 and could not be overcome by costimulation with anti-CD28 antibody. However, MAIDS CD4+ T cells failed to activate the PIP2 hydrolysis pathway efficiently, resulting in diminished IP3 production and reduced Ca2+ mobilization compared to normal controls. Additionally, TCR signaling in MAIDS resulted in a reduction in the level of tyrosine phosphorylation of some proteins including deficient tyrosine phosphorylation of PLC-gamma 1, compared to normal CD4+ T cells. These studies suggest that stimulation through the TCR in CD4+ T cells from MAIDS-infected mice is uncoupled from the phosphotidylinositol hydrolysis pathway due to deficient activation of PLC-gamma 1.
Fitzpatrick
E A
EA
Department of Microbiology and Immunology, University of Kentucky, Lexington 40536-0084, USA.
Kaplan
A M
AM
Cohen
D A
DA
D000818:Animals; D018106:CD28 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D005260:Female; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D016183:Murine Acquired Immunodeficiency Syndrome / Q000276:immunology*; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D019000:Phosphotyrosine / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism
D018106:CD28 Antigens; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D011948:Receptors, Antigen, T-Cell; D019000:Phosphotyrosine; D015759:Ionomycin; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium