Tetraspan microdomains distinct from lipid rafts enrich select peptide-MHC class II complexes.

Complexes of peptide and major histocompatibility complex (MHC) class II are expressed on the surface of antigen-presenting cells but their molecular organization is unknown. Here we show that subsets of MHC class II molecules localize to membrane microdomains together with tetraspan proteins, the peptide editor HLA-DM and the costimulator CD86. Tetraspan microdomains differ from other membrane areas such as lipid rafts, as they enrich MHC class II molecules carrying a selected set of peptide antigens. Antigen-presenting cells deficient in tetraspan microdomains have a reduced capacity to activate CD4+ T cells. Thus, the organization of uniformly loaded peptide-MHC class II complexes in tetraspan domains may be a very early event that determines both the composition of the immunological synapse and the quality of the subsequent T helper cell response.