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C3 opsonization regulates endocytic handling of apoptotic cells resulting in enhanced T-cell responses to cargo-derived antigens

Significance Activation of the complement system, a network of circulating and surface-bound molecules, is known to enhance humoral immunity. However, paradoxically, the lack of some complement components (mainly C1q and C4), but not C3, is associated with the development of autoimmunity. Prior studies have suggested that this association could be explained by the role of complement in the disposal of dying cells that are a potential source of autoantigens. This study demonstrates that C3 bound to dying cells can direct the intracellular route of the cargo and modulate the subsequent T-cell response to antigens displayed on dying cells. These results uncover a new role of C3 and have important implications for our understanding of the role of complement in health and disease. Apoptotic cells are a source of autoantigens and impairment of their removal contributes to the development of autoimmunity in C1q deficiency. However, the lack of complement component 3 (C3), the predominant complement opsonin, does not predispose to autoimmunity, suggesting a modifying role of C3 in disease pathogenesis. To explore this hypothesis, here we investigated the role of C3 in the T-cell response to apoptotic cell-associated antigens. By comparing the phagosome maturation and the subsequent MHC class II presentation of a peptide derived from the internalized cargo between C3-deficient or C3-sufficient dendritic cells, we found that C3 deficiency accelerated the fusion of the apoptotic cargo with lysosomes. As a result, C3 deficiency led to impaired antigen-specific T-cell proliferation in vitro and in vivo. Notably, preopsonization of the apoptotic cells with C3 activation fragments rectified the trafficking and T-cell stimulation defects. These data indicate that activated C3 may act as a “chaperone” in the intracellular processing of an apoptotic cargo and, thus, may modulate the T-cell response to self-antigens displayed on dying cells.