The p35 human invariant chain in transgenic mice restores mature B cells in the absence of endogenous CD74.

The invariant chain (Ii; CD74) has pleiotropic functions and Ii-deficient mice show defects in MHC class II (MHC II) transport and B cell maturation. In humans, but not in mice, a minor Iip35 isoform of unknown function includes an endoplasmic reticulum-retention motif that is masked upon binding of MHC II molecules. To gain further insight into the roles of Ii in B cell homeostasis, we generated Iip35 transgenic mice (Tgp35) and bred these with mice deficient for Ii (Tgp35/mIiKO). Iip35 was shown to compete with mIi for the binding to I-A(b) . In addition, classical endosomal degradation products (p20/p10) and the class II-associated invariant chain peptide (CLIP) fragment were detected. Moreover, Iip35 favored the formation of compact peptide-MHC II complexes in the Tgp35/mIiKO mice. I-A(b) levels were restored at the plasma membrane of mature B cells but Iip35 affected the fine conformation of MHC II molecules as judged by the increased reactivity of the AF6-120.1 antibody in permeabilized cells. However, the human Iip35 cannot fully replace the endogenous Ii. Indeed, most immature B cells in the bone marrow and spleen of transgenic mice had reduced surface expression of MHC II molecules, demonstrating a dominant-negative effect of Iip35 in Tgp35 mice. Interestingly, while maturation to follicular B cells was normal, Iip35 expression appeared to reduce the proportions of marginal zone B cells. These results emphasize the importance of Ii in B cell homeostasis and suggest that Iip35 could have regulatory functions.