FcRn regulates antigen presentation in dendritic cells downstream of DEC205-targeted vaccines
Christophe Macri,
Matthew Paxman,
Devi Jenika,
Xiao Peng Lin,
Zahra Elahi,
Paul A. Gleeson,
Irina Caminschi,
Mireille H. Lahoud,
Jose A. Villadangos,
Justine D. Mintern
Affiliations
Christophe Macri
Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Rd, Parkville, The University of Melbourne
Matthew Paxman
Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Rd, Parkville, The University of Melbourne
Devi Jenika
Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Rd, Parkville, The University of Melbourne
Xiao Peng Lin
Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Rd, Parkville, The University of Melbourne
Zahra Elahi
Department of Anatomy and Physiology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville
Paul A. Gleeson
Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Rd, Parkville, The University of Melbourne
Irina Caminschi
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville
Mireille H. Lahoud
Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton
Jose A. Villadangos
Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Rd, Parkville, The University of Melbourne
Justine D. Mintern
Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Rd, Parkville, The University of Melbourne
Abstract Dendritic cell (DC)-targeted vaccination is a new mode of antigen delivery that relies on the use of monoclonal antibodies (mAb) to target antigen to specific DC subsets. The neonatal Fc receptor (FcRn) is a non-classical Fc receptor that binds to immunoglobulin G (IgG) in acidified endosomes and controls its intracellular transport and recycling. FcRn is known to participate in the antigen presentation of immune complexes, however its contribution to DC-targeted vaccination has not previously been examined. Here we have investigated the role of FcRn in antigen presentation using antigen conjugated to IgG mAb which target specific DC receptors, including DEC205 and Clec9A expressed by the conventional DC 1 (cDC1) subset. We show that FcRn is expressed at high levels by cDC1, both at steady-state and following activation and plays a significant role in MHC I cross-presentation and MHC II presentation of antigens that are targeted to cDC1 via mAb specific for DEC205. This effect of FcRn is intrinsic to cDC1 and FcRn impacts the efficacy of anti-DEC205-mediated vaccination against B cell lymphoma. In contrast, FcRn does not impact presentation of antigens targeted to Clec9A and does not regulate presentation of cell-associated antigen. These data highlight a new and unique role of FcRn in controlling the immunogenicity of anti-DEC205-based vaccination, with consequences for exploiting this pathway to improve DC-targeted vaccine outcomes.
