Altered major histocompatibility complex class II peptide loading in H2-O-deficient mice

The biosynthesis of MHC class II/peptide complexes involves classical, cell surface MHC products as well as the intracellular component H2-M, required for the removal of invariant chain-derived CLIP and for peptide loading. T he function of another intracellular class II heterodimer, H2-O, is the mat ter of some controversy. The physical association of H2-O with H2-M and co- localization in class II+ vesicles suggest a related function in peptide ex change. Furthermore, the distinctive thymic distribution of H2-O raises the possibility of a specialized role in T cell thymic selection. To investiga te the role of H2-O in vivo we generated mice carrying a targeted disruptio n in the H2-Oa gene, No evidence was obtained for a defect in removal of CL IP. However, the array of endogenous peptides bound by class II was altered and a defect in antigen presentation through H2-A to T cells was seen on t he 129/Sv/C57BL/6 mixed strain background but not in 129/Sv pure strain mic e. Furthermore, H2-Onull mice showed enhanced selection of CD4(+) single po sitive thymocytes. The findings indicate that H2-O interacts with H2-M in p eptide editing but that the genetic background in which H2-O deficiency is manifest is also important. Overall, the experiments indicate that H2-O/HLA -DO should be regarded as neither up-regulating nor down-regulating the DM- dependent release of CLIP, but as a modulator of peptide editing, determini ng the presenting cell type specific peptide profile able to retain stabili ty in the class II groove.