INVARIANT CHAIN-INDEPENDENT FUNCTION OF H-2M IN THE FORMATION OF ENDOGENOUS PEPTIDE MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II COMPLEXES IN-VIVO

Efficient loading of major histocompatibility complex class II molecul es with peptides requires the invariant chain (Ii) and the class II-li ke molecule H-2M. Recent in vitro biochemical studies suggest that H2- M may function as a chapel-one to rescue empty class II dimers. To tes t this hypothesis in vivo, we generated mice lacking both Ii and H-2M (Ii(-/-)M(-/-)). Antigen presenting cells (APCs) from Ii(-/-)M(-/-) mi ce, as compared with APCs from Ii(-/-) mice, exhibit a significant red uction in their ability to present self-peptides to a panel of class I I I-A(b)-restricted T cells. As a consequence of this defect in the lo ading of self peptides, CD4(+) thymocyte development is profoundly imp aired in Ii(-/-)M(-/-) mice, resulting in a peripheral CD4(+) T cell p opulation with low levels of T cell receptor expression. These finding s are consistent with the idea that H-2M functions as a chaperone in t he peptide loading of class II molecules in vivo.