MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I PRESENTATION OF PEPTIDES DERIVED FROM SOLUBLE EXOGENOUS ANTIGEN BY A SUBSET OF CELLS ENGAGED IN PHAGOCYTOSIS

Major histocompatibility complex (MHC) class I molecules generally pre sent peptides derived from cytoplasmic proteins, but recent reports ha ve suggested that macrophages (MO) may be uniquely able to present exo genous antigens via these molecules, and that particle-associated anti gens show a marked increase in the efficiency of such presentation. We confirm here that particle uptake by MO permits exogenous ovaalbumin (OVA) to gain access to the endogenous class I processing pathway, an event that occurs rarely, if at all, in the absence of phagocytic stim uli. Presentation of soluble protein antigens by MHC class I molecules , however, is not limited to MCD, nor is direct coupling of antigen to the particle required. A variety of unconjugated particles promoted p resentation of simultaneously offered soluble OVA to K-b-restricted T cells by both MO and non-MO antigen-presenting cells (APC), provided t he latter could phagocytose the particles. Enhancement of presentation by phagocytic stimuli could not be explained by greater delivery of s oluble antigen to endosomal compartments because such stimuli did not increase soluble tracer accumulation, nor did they improve presentatio n of OVA to an MHC class II-restricted T cell hybridoma. OVA presentat ion induced by cophagocytosis of particles and free antigen was nevert heless very inefficient in comparison to presentation of OVA peptide, and even modest responses required high concentrations of protein and particles. Furthermore, only a fraction of APC exposed to OVA and part icles were lysed by anti-OVA cytotoxic T lymphocytes, despite virtuall y all cells showing OVA accumulation, particle uptake, and K-b express ion. Titration experiments were most consistent with a model in which, by disrupting membrane integrity, phagocytic overload (''indigestion' ') allows escape of OVA into the cytosol of some APC, rather than with a model in which phagocytosis activates a novel antigen processing pa thway that has evolved to permit class I loading of exogenous antigen. These data suggest caution in the development of vaccine strategies b ased on use of particle conjugates for elicitation of CD8(+) T cell im munity, but, at the same time, may be relevant to understanding class I-restricted responses to some intracellular pathogens normally reside nt in membrane-bound vesicles.