An intracellular self protein synthesized in macrophages is presented but fails to induce tolerance

Mice deficient for the fifth component of murine complement (C5), unlike normal mice, do not possess the secreted form of C5 in their body fluids and can be readily immunized to serum-derived normal C5. Although macrophages from C5-deficient mice do not secrete C5, they synthesize the precursor form (pro-C5). Therefore contact of T cells with autologous pro-C5 presented by macrophages is theoretically possible. We show that macrophages from C5-deficient mice can indeed stimulate a class II restricted C5-specific T cell clone without addition of exogenous C5. Immunization of C5-deficient mice with autologous pro-C5 induces vigorous C5-specific T cell proliferation and pro-C5 is recognized by C5-specific T cells in vitro, demonstrating that this protein fails to induce tolerance under physiological conditions. Thus, intracellular pro-C5 is processed and presented by C5-deficient macrophages and can activate T cell clones in vitro, yet is neither immunogenic nor tolerogenic for T cells in vivo.