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

doi:10.1084/jem.182.3.779

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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

R Konig, X Shen and RN Germain
Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston 77555-1019, USA.

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.
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