The CD4 molecule is expressed on a subset of T lymphocytes which recognize their cognate antigen in the context of MHC class II molecules. It is widely accepted that the interaction between CD4 and MHC class II molecules enhances T cell response to specific antigen. CD4 is non-covalently associated with the src-related tyrosine kinase p56$ rm sp{lck}.$ Using the T cell clone 2.10, we have shown that CD4 can sequester lck and inhibit anti-TcR induced proliferation if not co-aggregated with the TcR. Our results suggest that MHC class II molecules through their simultaneous interaction with the TcR and CD4 potentiate T cell activation by bringing the CD4/lck complex to the proximity of the TcR. This cellular system was also used to demonstrate that the extracellular domain of CD4 can also regulate the initiation of T cell activation independently of its interaction with MHC class II molecules. Indeed, cells expressing chimeric molecules composed of the epidermal growth factor receptor (EGFR) extracellular domain and the CD4 cytoplasmic tail were still responding to anti-TcR simulation in the absence of co-aggregation. The role of the extracellular domain of CD4 was further demonstrated in experiments in which the HIV-1 envelope glycoprotein gp120 was used to inhibit antigenic stimulation of CD4-independent T cell responses. This inhibition was occurring whether CD4 is associated with lck or not, suggesting that gp120 is modulating a CD4 function other than association with lck and which is related to its extracellular portion. In addition to its effect on T cell activation, interaction between gp120 and CD4 modulates HIV replication at a post-transcriptional level. The CD4/lck association is required for this effect as the virus replicates much more efficiently in cells bearing a CD4 which is not associated with lck. Activation of lck through the CD4/gp120 interaction may thus be responsible for the induction of latency. Nef, another HIV protein playing a critical r
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.39912 |
| Date | January 1995 |
| Creators | Gratton, Sophie |
| Contributors | Sekaly, Rafick-Pierre (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001480982, proquestno: NN12376, Theses scanned by UMI/ProQuest. |
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