The role of H2-O and HLA-DO in major histocompatibility complex class II-restricted antigen processing and presentation

The function of major histocompatibility complex (MHC) class II molecules i s to sample exogenous antigens for presentation to CD4(+) T helper cells. A fter synthesis in the endoplasmic reticulum, class II molecules are directe d into the endosomal system by association with the invariant chain (Ii), w hich is sequentially cleaved, generating class II dimers loaded with Ii-der ived peptides (CLIP). These class II-peptide complexes are physiological su bstrates for H2-M/HLA-DM, a resident of the endosomal/lysosomal system whic h facilitates the removal of CLIP from newly synthesised class II ap dimers . Exchange of CLIP for antigenic class II-binding peptides is also promoted by the action of H2-M/HLA-DM, resulting in stable peptide-class II complex es that are transported to the cell surface for presentation to CD4(+) T ce lls. Recent evidence suggests that this H2-M/HLA-DM-mediated 'peptide editi ng' is influenced by another MHC class II-encoded molecule, H2-O/HLA-DO. Th is non-polymorphic ap heterodimer is associated with H2-M/HLA-DM during int racellular transport and within the endosomal system of B cells. H2-O/HLA-D O alters the peptide exchange function of H2-M/HLA-DM in a pH-dependent man ner, so that H2-M/HLA-DM activity is limited to more acidic conditions, cor responding to lysosomal compartments. Indeed, H2-O/HLA-DO may serve to limi t the presentation of antigens after fluid phase uptake by B cells, while a ugmenting presentation of antigens internalised via membrane Ig receptors. Such a mechanism may maintain the fidelity of the B-cell-CD4(+) T-cell inte raction, counteracting self reactivity arising from less stringent lymphocy te activation. Here, data evaluating the role of H2-O/HW-DO shall be review ed and its putative function discussed.