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 molecules with peptides requires the invariant chain (Ii) and the class II–like molecule H-2M. Recent in vitro biochemical studies suggest that H2-M may function as a chaperone to rescue empty class II dimers. To test this hypothesis in vivo, we generated mice lacking both Ii and H-2M (Ii(−/−)M(−/−)). Antigen presenting cells (APCs) from Ii(−/−)M(−/−) mice, as compared with APCs from Ii(−/−) mice, exhibit a significant reduction in their ability to present self-peptides to a panel of class II I-A(b)–restricted T cells. As a consequence of this defect in the loading of self peptides, CD4(+) thymocyte development is profoundly impaired in Ii(−/−)M(−/−) mice, resulting in a peripheral CD4(+) T cell population with low levels of T cell receptor expression. These findings are consistent with the idea that H-2M functions as a chaperone in the peptide loading of class II molecules in vivo.