Involvement of both major histocompatibility complex class II alpha and beta chains in CD4 function indicates a role for ordered oligomerization in T cell activation.
CD4 is a membrane glycoprotein on T lymphocytes that binds to the same peptide:major histocompatibility complex (MHC) class II molecule recognized by the antigen-specific receptor (TCR), thereby stabilizing interactions between the TCR and peptide;MHC class II complexes and promoting the localization of the src family tyrosine kinase p56lck into the receptor complex. Previous studies identified a solvent-exposed loop on the class II beta 2 domain necessary for binding to CD4 and for eliciting CD4 coreceptor activity. Here, we demonstrate that a second surface-exposed segment of class II is also critical for CD4 function. This site is in the alpha 2 domain, positioned in single class II heterodimers in such a way that it cannot simultaneously interact with the same CD4 molecule as the beta 2 site. The ability of mutations at either site to diminish CD4 function therefore indicates that specifically organized CD4 and/or MHC class II oligomers play a critical role in coreceptor-dependent T cell activation.
König
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Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston 77555-1019, USA.
Shen
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Germain
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D000818:Animals; D001665:Binding Sites; D015704:CD4 Antigens / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D005802:Genes, MHC Class II; D006681:HLA-D Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection
D015704:CD4 Antigens; D018076:DNA, Complementary; D006681:HLA-D Antigens