The Crystal Structure of CD8 in Complex with YTS156.7.7 Fab and Interaction with Other CD8 Antibodies Define the Binding Mode of CD8 αβ to MHC Class I

[摘要] The CD8 alpha beta heterodimer interacts with class I pMHC on antigen-presenting cells as a co-receptor for TCR-mediated activation of cytotoxic T cells. To characterize this immunologically important interaction, we used monoclonal antibodies (mAbs) specific to either CD8 alpha or CD8 beta to probe the mechanism of CD8 alpha beta binding to pMHCI. The YTS156.7 mAb inhibits thus interaction and blocks T cell activation. To elucidate the molecular basis for this inhibition, the crystal structure of the CD8 alpha beta immunoglobulin-like ectodomains were determined in complex with mAb YTS156.7 Fab at 2.7 angstrom resolution. The YTS156.7 epitope on CD8 beta was identified and implies that residues in the CDR1 and CDR2-equivalent loops of CD8 beta are occluded upon binding to class I pMHC. To further characterize the pMHCI/CD8 alpha beta interaction, binding of class I tetramers to CD8 alpha beta on the surface of T cells was assessed in the presence of anti-CD8 mAbs. In contrast to YTS156.7, mAb YTS105.18, which is specific for CD8a, does not inhibit binding of CD8 alpha beta to class I tetramers, indicating the YTS105.18 epitope is not occluded in the pMHCI/CD8 alpha beta complex. Together, these data indicate a model for the pMHCI/CD8 alpha beta interaction similar to that observed for CD8 alpha alpha in the CD8 alpha alpha/pMHCI complex, but in which CD8a occupies the lower orientation (membrane proximal to the antigen presenting cell), and CD8 beta occupies the upper position (membrane distal). The implication of thus molecular assembly for the function of CD8 alpha beta in T cell activation is discussed. (C) 2008 Elsevier Ltd. All rights reserved.

[发布日期] 2008-12-31

[关键词] CD8 alpha G beta;TCR co-receptor;antibody complex;T cell;crystal structure