MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II-RESTRICTED PRESENTATION OF AN INTERNALLY SYNTHESIZED ANTIGEN DISPLAYS CELL-TYPE VARIABILITY AND SEGREGATES FROM THE EXOGENOUS CLASS-II AND ENDOGENOUS CLASS-I PRESENTATION PATHWAYS

Although reported examples of endogenous antigen (Ag) presentation by major histocompatibility complex (MHC) class II molecules have increas ed, the mechanisms governing this process remain poorly defined. In th is communication, we describe an experimental system designed to exami ne the mechanisms governing class II presentation of internal Ag. Our target peptide is processed from a transmembrane protein constitutivel y expressed by a variety of nucleated cells (MHC class I, H-2L(d)), is naturally displayed by MHC class II molecules in vivo, and is recogni zed by a class II-restricted, CD4+ T cell hybridoma. Our results indic ate that presentation of the L(d) target Ag is independent of its plas ma membrane expression, may not involve endosomal proteolysis, and thu s may be distinct from the classically defined class II presentation p athway. In addition, the observations that L(d) presentation does not require a functional TAP-1 complex, is not blocked by invariant chain, and cannot utilize cytoplasmic forms of H-2L(d), suggest that a class ical class I pathway is not involved in this presentation event. Final ly, our data suggest that different cofactors participate in MHC class II presentation of exogenous and endogenous Ag, and that disparate Ag presenting cells, such as B, T, and pancreatic islet cells, may diffe rentially express these two class II pathways of Ag presentation.