Macrophage presentation of endogenous self-protein: the MHC class II presentation pathway is not accessible to intracellular C5 or alpha 1-antitrypsin

Abstract

This paper addresses the question of whether macrophages can present biosynthesized protein in a class II-restricted manner using the endogenous rather than the exogenous pathway of presentation. Two distinct self-antigens, the fifth component of complement (C5) and alpha 1-antitrypsin, were studied. Both antigens are serum proteins synthesized by hepatocytes and macrophages. To direct synthesis exclusively to macrophages chimeras were constructed by transfer of bone marrow from donors expressing the self-antigen into irradiated hosts deficient for the respective self-antigen. Macrophages from such mice were unable to present biosynthesized C5 to class II-restricted T cells, even when preactivated 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 C5. Nevertheless, macrophage-synthesized alpha 1-antitrypsin in bone marrow chimeras was not presented in the context of class II--even in a mutant form which is sequestered in high amounts in the endoplasmic reticulum. We conclude that macrophages are unable to use the endogenous class II 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 macrophages and are neither tolerized nor rendered autoimmune.