AbstractThe fifth component of complement (C5) is a self antigen expressed in serum of normal mice at a concentration of about 50 μg/ml. We have previously shown that C5 is constitutively processed and presented by antigen‐presenting cells (APC) in normal mice to induce and maintain complete tolerance in major histocompatibility complex (MHC) class II‐restricted T cells. This report addresses the question of whether C5 presentation involves exogenous antigen which has been internalized for processing or whether intracellular, biosynthesized C5 is being presented with MHC class II. Macrophages were found to synthesize, but not secrete C5 in bone marrow chimeras made from irradiated C5‐deficient [C5(−)] hosts reconstituted with C5‐sufficient [C5(+)]bone marrow [C5(+) ← C5(−)]. In these mice, macrophages are the only source of C5. [C5(+) ← C5(−)]chimeras are not tolerant of C5 and generate C5‐specific T and B cell responses upon immunization indistinguishable from those of C5(‐) mice. Macrophages from [C5(+) ← C5(‐)] chimeras are unable to activate C5‐specific T cell hybridsin vitrounlike macrophages from a C5(−) strain that has matured in a C5‐expressing environment [C5(−) ← C5(+) chimeras]. This shows that under physiological conditionsin vivointracellular C5 does not get access to the class II presentation pathway and thus, does not induce tole