Mice lacking C1q or C3 show accelerated rejection of minor H disparate skin grafts and resistance to induction of tolerance

• Published in: European journal of immunology 2010-06, Vol.40 (6), p.1758-1767
• Main Authors: Baruah, Paramita, Simpson, Elizabeth, Dumitriu, Ingrid E, Derbyshire, Katy, Coe, David, Addey, Caroline, Dyson, Julian, Chai, Jian-Guo, Cook, Terence, Scott, Diane, Botto, Marina
• Format: Article
• Language: English
• Subjects: Administration, Intranasal; Animals; CD8-Positive T-Lymphocytes - immunology; Complement; Complement C1q - deficiency; Complement C1q - immunology; Complement C3 - deficiency; Complement C3 - immunology; Cytokines - biosynthesis; Cytokines - immunology; Enzyme-Linked Immunosorbent Assay; Female; Females; Graft Rejection - immunology; H-Y Antigen - administration & dosage; H-Y Antigen - immunology; Innate Immunity; Interferon-gamma - immunology; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Peptides; Plastic surgery; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Skin graft; Skin Transplantation - immunology; Tolerance; Transplantation, Homologous - immunology
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200940158

Complement activation is known to have deleterious effects on organ transplantation. On the other hand, the complement system is also known to have an important role in regulating immune responses. The balance between these two opposing effects is critical in the context of transplantation. Here, we report that female mice deficient in C1q (C1qa⁻/⁻) or C3 (C3⁻/⁻) reject male syngeneic grafts (HY incompatible) at an accelerated rate compared with WT mice. Intranasal HY peptide administration, which induces tolerance to syngeneic male grafts in WT mice, fails to induce tolerance in C1qa⁻/⁻ or C3⁻/⁻ mice. The rejection of the male grafts correlated with the presence of HY DbUty-specific CD8⁺ T cells. Consistent with this, peptide-treated C1qa⁻/⁻ and C3⁻/⁻ female mice rejecting male grafts exhibited more antigen-specific CD8⁺IFN-γ⁺ and CD8⁺IL-10⁺ cells compared with WT females. This suggests that accumulation of IFN-γ- and IL-10-producing T cells may play a key role in mediating the ongoing inflammatory process and graft rejection. Interestingly, within the tolerized male skin grafts of peptide-treated WT mice, IFN-γ, C1q and C3 mRNA levels were higher compared to control female grafts. These results suggest that C1q and C3 facilitate the induction of intranasal tolerance.