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-Chain Enhances the Coreceptor Function of CD81
Dana-Farber Cancer Institute, Department of Cancer Immunology and AIDS, Harvard Medical School, Boston, MA 02115
CD8 glycoproteins are expressed as either 
homodimers or 
heterodimers on the surface of T cells. CD8 is a more efficient coreceptor than the CD8 for peptide Ag recognition by TCR. Each CD8 subunit is composed of four structural domains, namely, Ig-like domain, stalk region, transmembrane region, and cytoplasmic domain. In an attempt to understand why CD8 is a better coreceptor than CD8, we engineered, expressed, and functionally tested a chimeric CD8 protein whose stalk region is replaced with that of CD8. We found that the stalk region enhances the coreceptor function of chimeric CD8 to a level similar to that of CD8. Surprisingly, the stalk region also restored functional activity to an inactive CD8 variant, carrying an Ala mutation at Arg8 (R8A), to a level similar to that of wild-type CD8. Using the R8A variant of CD8, a panel of anti-CD8 Abs, and three MHC class I (MHCI) variants differing in key residues known to be involved in CD8 interaction, we show that the introduction of the CD8 stalk leads to a different topology of the CD8-MHCI complex without altering the overall structure of the Ig-like domain of CD8 or causing the MHCI to employ different residues to interact with the CD8 Ig domain. Our results show that the stalk region of CD8 is capable of fine-tuning the coreceptor function of CD8 proteins as a coreceptor, possibly due to its distinct protein structure, smaller physical size and the unique glycan adducts associated with this region.
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