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. The function of another intracellular class II heterodimer, H2‐O, is the matter 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 exchange. Furthermore, the distinctive thymic distribution of H2‐O raises the possibility of a specialized role in T cell thymic selection. To investigate the role of H2‐O in vivo we generated mice carrying a targeted disruption in the H2‐Oa gene. No evidence was obtained for a defect in removal of CLIP. 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 the 129/Sv/C57BL/6 mixed strain background but not in 129/Sv pure strain mice. Furthermore, H2‐O‐null mice showed enhanced selection of CD4+ single positive thymocytes. The findings indicate that H2‐O interacts with H2‐M in peptide 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, determining the presenting cell type specific peptide profile able to retain stability in the class II groove.

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