CD8 raft localization is induced by its assembly into CD8αβ heterodimers, not CD8αα homodimers

The coreceptor CD8 is expressed as a CD8 alpha beta heterodimer on major histocompatibility complex class I-restricted TCR alpha beta T cells, and as a CD8 alpha alpha homodimer on subsets of memory T cells, intraepithelial lymphocytes, natural killer cells, and dendritic cells. Although the role of CD8 alpha alpha is not well understood, it is increasingly clear that this protein is not a functional homologue of CD8 alpha beta On major histocompatibility complex class I-restricted T cells, CD8 alpha beta is a more efficient TCR coreceptor than CD8 alpha alpha. This property has for the mouse protein been attributed to the recruitment of CD8 alpha beta into lipid rafts, which is dependent on CD8 beta palmitoylation. Here, these divergent distributions of CD8 alpha beta and CD8 alpha alpha are demonstrated for the human CD8 proteins as well. However, although palmitoylation of both CD8 alpha and CD8 beta chains was detected, this modification did not contribute to raft localization. In contrast, arginines in the cytoplasmic domain are crucial for raft localization of CD8 beta beta. Most strikingly, the assembly of a non-raft localized CD8 beta chain with a non-raft localized CD8 alpha chain resulted in raft-localized CD8 alpha beta heterodimers. Using chimeric CD8 proteins, this property of the heterodimer was found to be determined by the assembly of CD8 alpha and CD8 beta extracellular regions. The presence of two CD8 alpha extracellular regions, on the other hand, appears to preclude raft localization. Thus, heterodimer formation and raft association are intimately linked for CD8 alpha beta. These results emphasize that lipid raft localization is a key feature of human CD8 alpha beta that clearly distinguishes it from CD8 alpha alpha.