H2-M MUTANT MICE ARE DEFECTIVE IN THE PEPTIDE LOADING OF CLASS-II MOLECULES, ANTIGEN PRESENTATION, AND T-CELL REPERTOIRE SELECTION

H2-M is a nonconventional major histocompatibility complex (MHC) class II molecule that has been implicated in the loading of peptides onto conventional class II molecules. We generated mice with a targeted mut ation in the H2-Ma gene, which encodes a subunit for H2-M. Although th e mutant mice express normal class II cell surface levels, these are s tructurally distinct from the compact SDS-resistant complexes expresse d by wild-type cells and are predominantly bound by class II-associate d invariant chain peptides (CLIPs). Cells from these animals are unabl e to present intact protein antigens to class II-restricted T cells an d show reduced capacity to present exogenous peptides. Numbers of matu re CD4(+) T lymphocytes in mutant mice are reduced 3- to 4-fold and ex hibit altered reactivities. Overall, this phenotype establishes an imp ortant role for H2-M in regulating MHC class II function in vivo and s upports the notion that self-peptides contribute to the specificity of T cell positive selection.