Modulation of CD4+ T cell responses by CD59a

• Main Author: Longhi, Maria Paula
• Published: Cardiff University 2006
• Subjects: 615
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.583895

CD59 is a GPI-anchored protein found in membrane microdomains known as lipid rafts. It is a complement regulator protein, which blocks the formation of the membrane attack complex by inhibiting binding of C9 to the C5-8 complex. Human CD59 has also been described as a co-stimulator of T cell activation. The aim of this project was to analyze the role of CD59 on T cell activation in vivo. For this purpose, anti-viral CD4+ T cell responses were analyzed in mice deficient in the mouse analogue of CD59 CD59a. Infection with recombinant vaccinia virus (rVV) and influenza virus, resulted in stronger virus-specific CD4+ T cell responses in Cd59a -/- mice compared to WT mice. This effect, which indicates that CD59a downmodulates antigen-specific T cell activity, was found to be complement independent. Experiments were performed to investigate the effect of CD59 expression on human CD4+ T cells. Blocking CD59 increased proliferation of the cells in vitro indicating that CD59 might similarly downmodulate human CD4+ T cell activity. Using mouse T cells, mechanisms underlying the effect of CD59a on CD4+ T cell activity were investigated. Results of these studies indicated that downmodulation of T cell activity through CD59a requires engagement of CD59a with a ligand expressed on APCs. To assess the biological consequences of CD59a deficiency, the extent of immunopathology induced following infection with influenza virus was compared in WT and Cd59a-/- mice. Immunopathology was exacerbated in Cd59a-/- mice, correlating with increased numbers of neutrophils and CD4+ T cells in infected lungs. When complement was inhibited, lung-infiltrating neutrophils in Cd59a-/- mice were much reduced while numbers of infiltrating-CD4+ T cell remained unchanged. These results demonstrate that CD59a is more than a regulator of complement but can in fact, alter both the innate and adaptive immune responses using both complement dependent and independent mechanisms.