MACROPHAGE PRESENTATION OF ENDOGENOUS SELF-PROTEIN - THE MHC CLASS-IIPRESENTATION PATHWAY IS NOT ACCESSIBLE TO INTRACELLULAR C5 OR ALPHA-1-ANTITRYPSIN

This paper addresses the question of whether macrophages can present b iosynthesized protein in a class II-restricted manner using the endoge nous rather than the exogenous pathway of presentation. Two distinct s elf-antigens, the fifth component of complement (C5) and alpha 1-antit rypsin, were studied. Both antigens are serum proteins synthesized by hepatocytes and macrophages. To direct synthesis exclusively to macrop hages chimeras were constructed by transfer of bone marrow from donors expressing the self-antigen into irradiated hosts deficient for the r espective self-antigen. Macrophages from such mice were unable to pres ent biosynthesized C5 to class II-restricted T cells, even when preact ivated in vivo. While C5 production by macrophages is low and may not reach critical levels of intracellular protein required to access the class II presentation pathway, human alpha 1-antitrypsin, expressed as a transgene in mice, was synthesized at 600-fold higher levels than C 5. Nevertheless, macrophage-synthesized alpha 1-antitrypsin in bone ma rrow chimeras was not presented in the context of class II-even in a m utant form which is sequestered in high amounts in the endoplasmic ret iculum. We conclude that macrophages are unable to use the endogenous class ZI presentation pathway for these two model self-antigens. As a consequence MHC class II-restricted T cells specific for C5 and alpha 1-antitrypsin remain ignorant of the presence of self-antigen within m acrophages and are neither tolerized nor rendered autoimmune. (C) 1996 Academic Press, Inc.