Improving antigen presentation by targeting antigens to dendritic cells

For the induction of both, primary and secondary immune responses, dendritic cells (DCs) are the most potent antigen presenting cells. Complement receptors (CRs) and Fcgamma-receptors (FcgammaRs) expressed on DCs are thought to be important in the binding and internalisation of antigens and were demonstrated to have an impact on DC functions regarding antigen presentation and thus induction of T cell responses. Due to the deposition of complement fragments and/or antibodies on the viral surface, such complement- and complement-IgG opsonized virions are able to interact with CRs and FcgammaRs expressed on DCs. In this proposal, we will utilize the Friend virus (FV) model, as this murine retrovirus represents a well established experimental model to study in vivo mechanisms of the immune response against a retroviral infection. Our preliminary experiments strongly suggest that C- and IgG-opsonisation of FV has an impact on both, infection and antigen presentation of bone-marrow derived DCs. Therefore, in this study we will in detail characterise the role of complement- and Fcgamma- receptors regarding this process. Furthermore, we will investigate the potential of targeting retroviral antigens to complement- and Fcgamma-receptors on DCs to improve their antigen presentation.

Complement belongs to the innate immune system, which takes a part in the immediate response against invading pathogens. Although complement (C) is a powerful effector mechanism destroying pathogens by complement-mediated lysis (CML), retroviruses like HIV and the Friend Murine Leukemia Virus (F-MuLV) are protected from CML. Thus, retroviruses are not destroyed by CML, but they accumulate C-fragments on their surface. Such C-fragments can then interact with complement receptors (CR) expressed on the surface of antigen presenting cells like dendritic cells (DC). DCs are important players in the induction of adaptive immune responses. Thus, in this research project we investigated the involvement of complement in the DC-mediated induction of immune responses against retroviral infections. We found that C acts as an endogenous adjuvant for activation of specific T cells by DCs. We also proofed the potential of targeting antigens to CRs on DCs to improve antigen presentation. We showed that targeting viral antigens to DC by antibody- derived molecules recognizing CRs could improve the induction of specific T cell responses both in vitro and in vivo. Since the induction of strong virus-specific T cell responses is critical in viral infections, DC targeted protein vaccines might provide means to enhance the cellular immune response to prophylactic or therapeutic levels.