Title : The crystal
structure of CD8 in complex with YTS156.7.7 Fab and interaction with other
CD8 antibodies define the binding mode of
CD8 alphabeta to MHC class I
Abstract :
- The CD8alphabeta 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 CD8alpha or CD8beta to probe the mechanism of CD8alphabeta binding to pMHCI
- The YTS156.7 mAb inhibits this interaction and blocks T cell activation
- To elucidate the molecular basis for this inhibition, the crystal structure of the CD8alphabeta immunoglobulin-like ectodomains were determined in complex with mAb YTS156.7 Fab at 2.7 A resolution
- The YTS156.7 epitope on CD8beta was identified and implies that residues in the CDR1 and CDR2-equivalent loops of CD8beta are occluded upon binding to class I pMHC
- To further characterize the pMHCI/CD8alphabeta interaction, binding of class I tetramers to CD8alphabeta 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 CD8alpha , does not inhibit binding of CD8alphabeta to class I tetramers, indicating the YTS105.18 epitope is not occluded in the pMHCI/CD8alphabeta complex
- Together, these data indicate a model for the pMHCI/CD8alphabeta interaction similar to that observed for CD8alphaalpha in the CD8alphaalpha/pMHCI complex, but in which CD8alpha occupies the lower orientation (membrane proximal to the antigen presenting cell), and CD8beta occupies the upper position (membrane distal)
- The implication of this molecular assembly for the function of CD8alphabeta in T cell activation is discussed