Functional in vivo MHC class II loading by endogenously synthesized glycoprotein during viral infection.

Abstract

MHC class II presentation of antigenic peptides derived from soluble proteins is usually preceded by antigenic uptake via (nonreceptor-mediated) endocytosis by professional APCs, followed by processing in endosomal compartments. Although in vitro alternative pathways for MHC class II loading have been described for certain intracellularly synthesized proteins, the importance of these pathways has not been assessed in vivo. We have shown previously that endogenously produced membrane-associated glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), a noncytopathic virus, can be presented in vitro on MHC class II molecules in the absence of the invariant chain (Ii), whereas the cytosolic LCMV nucleoprotein (LCMV-NP) failed to be presented under the same conditions. Taking advantage of this system, we analyzed presentation of LCMV-GP and LCMV-NP in vivo in Ii-deficient mice and followed the induced Th cell and B cell responses. At early time points after LCMV infection of li-deficient mice, we found in vivo MHC class II loading exclusively by the endogenously synthesized LCMV-GP, whereas no MHC class II loading by LCMV-NP could be detected. As a direct consequence, LCMV-specific Th cells exhibited initially only LCMV-GP specificity. In contrast, both LCMV-GP- and LCMV-NP-derived epitopes were presented in comparable amounts on APCs upon LCMV infection of normal mice, and LCMV-GP- as well as LCMV-NP-specific Th cells were comparably induced in vivo. Thus, cell internal MHC class II loading pathways are functional in vivo and may become dominant if the usual Ag presentation pathways are hampered.