C3 opsonization regulates endocytic handling of apoptotic cells resulting in enhanced T-cell responses to cargo-derived antigens.
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.
Department of Medicine, Division of Immunology and Inflammation, Centre for Complement and Inflammation Research and Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom.
Lucie
L
Baudino
Alessandro
A
Sardini
Marieta M
MM
Ruseva
Liliane
L
Fossati-Jimack
H Terence
HT
Cook
Diane
D
Scott
Elizabeth
E
Simpson
Marina
M
Botto
D000818:Animals; D017209:Apoptosis; D001324:Autoantigens / Q000276:immunology*; D003176:Complement C3 / Q000378:metabolism*; D004705:Endocytosis; D051379:Mice; D018345:Mice, Knockout; D009895:Opsonin Proteins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology
D001324:Autoantigens; D003176:Complement C3; D009895:Opsonin Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4