Complement Component 3 Is Required for Optimal Expansion of CD8 T Cells During a Systemic Viral Infection

Abstract

In addition to its established role in innate immune mechanisms, complement component C3 is also of critical importance in B cell activation and T cell-dependent Ab responses. In this study, we have examined the requirement for C3 in the generation of primary CD8 T cell responses to an acute systemic viral infection. We compared Ag-specific CD8 T cell responses to lymphocytic choriomeningitis virus (LCMV) between wild-type (+/+) and C3-deficient (C3−/−) mice on both 129/B6 and B6 backgrounds. These studies revealed that C3 activity is required for optimal expansion of LCMV-specific effector CD8 T cells in an epitope-dependent fashion, which is influenced by the genetic background of the mice. Studies in complement receptor 1/2 (CR1/CR2)-deficient mice showed that regulation of LCMV-specific CD8 T cell responses by C3 is not dependent upon CR1/CR2. These findings may have implications in vaccine development, therapy of autoimmune diseases, and prevention of graft rejection.

Complement Regulates CD4 T-Cell Help to CD8 T Cells Required for Murine Allograft Rejection

“…24 Similarly, antiviral CD8 cell responses are suboptimal in C3 Ϫ/Ϫ and C5aR Ϫ/Ϫ mice. [25][26][27] Together with our new data these published findings support the concept that local complement production links CD40-transmitted signals to APC activation but also suggest that complement-independent mechanisms contribute to CD40-induced, APC activation.…”

Bioluminescence imaging reveals a significant role for complement in liver transduction following intravenous delivery of adenovirus

“…In addition to benefits for tumor targeting, inhibition of complement activation may also have the added benefit of decreasing the humoral and cell mediated immune response to virus. 27 It is envisioned that future Ad vectors will display complement regulatory proteins on their surface, or other surface proteins capable of binding negative regulators of complement activation in host blood. Potential sites of incorporation of these proteins in the Ad include the hexon, or pIX, a recently demonstrated site for genetic addition of peptides.…”

The Vaccinia Virus Complement Control Protein Modulates Adaptive Immune Responses during Infection

“…Despite compelling evidence that complement activation enhances Ab and T cell responses (7,10,14,15,23,24,37,44,50,55,56), it is unknown whether inhibition of complement by pathogens can also limit adaptive immune responses. VCP has been characterized as a virulence factor (20), but the mechanisms by which it contributes to the pathogenesis of VACV in vivo have not been fully defined.…”

“…Complement has been shown to enhance Ab responses to several viruses, including herpes simplex virus (HSV) (7,14,15,55,56), vesicular stomatitis virus (VSV) (44), and West Nile virus (WNV) (37,38). Recently, it has become clear that complement is also important for eliciting optimal T cell responses to several viral pathogens (10,24,37,50). During viral infection, complement-deficient mice exhibit reduced expansion and accumulation of CD4 ϩ and CD8 ϩ T cells following infection with influenza virus (24), WNV (37), or lymphocytic choriomengitis virus (LCMV) (50).…”

“…Recently, it has become clear that complement is also important for eliciting optimal T cell responses to several viral pathogens (10,24,37,50). During viral infection, complement-deficient mice exhibit reduced expansion and accumulation of CD4 ϩ and CD8 ϩ T cells following infection with influenza virus (24), WNV (37), or lymphocytic choriomengitis virus (LCMV) (50). Consistent with these findings, deficiency in the mammalian complement regulatory protein Daf-1 results in increased complement activation, which leads to enhanced CD8 ϩ T cell responses following infection with LCMV (10).…”