Abstract
Recent reports suggest that complement system contributes to allograft rejection. However, its underlying mechanism is poorly understood. Herein, we investigate the role of complement component 3 (C3) in a single MHC-II molecule mismatched murine model of allograft rejection using C3 deficient mice (C3−/−) as skin graft donors or recipients. Compared with C3+/+ B6 allografts, C3−/− B6 grafts dramatically prolonged survival in MHC-II molecule mismatched H-2bm12 B6 recipients, indicating that C3 plays a critical role in allograft rejection. Compared with C3+/+ allografts, both Th17 cell infiltration and Th1/Th17 associated cytokine mRNA levels were clearly reduced in C3−/− allografts. Moreover, C3−/− allografts caused attenuated Th1/Th17 responses, but increased CD4+CD25+Foxp3+ regulatory T (Treg) cell expression markedly in local intragraft and H-2bm12 recipients. Depletion of Treg cells by anti-CD25 monoclonal antibody (mAb) negated the survival advantages conferred by C3 deficiency. Our results indicate for the first time that C3 deficiency can prolong MHC-II molecule mismatched skin allograft survival, which is further confirmed to be associated with increased CD4+ CD25+ Treg cell population expansion and attenuated Th1/Th17 response.
Highlights
Our results indicate for the first time that component 3 (C3) deficiency can prolong MHC-II molecule mismatched skin allograft survival, which is further confirmed to be associated with increased CD4+ CD25+ Treg cell population expansion and attenuated Th1/Th17 response
Full thickness tail skin from alloreactive C3+/+ B6 and C3−/− B6 mice was transplanted into MHC-II molecule disparate Bm12 recipients, and syngeneic Bm12 used as a negative control
Compared with C3+/+ allografts, which were completely rejected within 17 days after transplantation, 60% of C3−/− allografts survived until day 30 (Fig. 1a, p < 0.0001)
Summary
Our results indicate for the first time that C3 deficiency can prolong MHC-II molecule mismatched skin allograft survival, which is further confirmed to be associated with increased CD4+ CD25+ Treg cell population expansion and attenuated Th1/Th17 response. The complement system is one of the major contributors to innate immunity and contains a series of soluble and cell surface proteins, including plasma components, specific receptors and diverse regulators. The absence of C3aR and C5aR signalling in CD4+ T cells has recently been confirmed to favour Treg expansion and survival[25,26] It remains unclear how C3 affects Treg cells development and regulates the balance between Treg cells and Th1/ Th17 cells response during transplantation rejection
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