lck-independent inhibition of T cell antigen response by the HIV gp120.
Binding of the HIV envelope glycoprotein gp120 to CD4 inhibits T cell activation. We have used a murine T cell clone transfected with either wild-type human CD4 or mutated forms of CD4 to characterize the pathways involved in this inhibitory effect of gp120. Ag-induced proliferation of T cell clones transfected with human CD4 was completely inhibited in the presence of gp120, even though stimulation of this clone is independent of a CD4/MHC class II interaction. In addition, our results demonstrate that the inhibition by gp120 is not due to the sequestration of lck from TCR and does not require activation of lck by gp120. This suggests that CD4 can regulate the initiation of T cell activation independently of its interaction with lck. Moreover, we demonstrate that the nonresponsiveness induced by gp120 can be reversed by soluble CD4 when added early after onset of stimulation and that gp120 exerts its inhibitory effect when cells are in the G0 > or = 1 phase of the cell cycle.
Laboratoire d'Immunologie, Institut de Recherches Cliniques de Montréal, Québec, Canada.
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Gratton
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Julius
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Sékaly
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D015704:CD4 Antigens / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D002999:Clone Cells; D016193:G1 Phase / Q000187:drug effects / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016192:Resting Phase, Cell Cycle / Q000187:drug effects / Q000276:immunology; D012995:Solubility; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D014162:Transfection / Q000276:immunology
D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D007166:Immunosuppressive Agents; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)