FCRN MEDIATED MUCOSAL IMMUNITY AND SUBUNIT VACCINE DELIVERY

Abstract

FcRn, the neonatal Fc receptor, is an MHC class I related molecule, functions as an IgG protector and transporter. Binding of IgG by FcRn exclusively occurrs at acidic pH, in correlation with the fact that FcRn mainly resides in acidic endosomes. Herein, we found an association of FcRn with invariant chain (Ii). The interaction was initiated within the endoplasmic reticulum by Ii binding to either the FcRn heavy chain alone or heavy chain-beta-2-microglobulin complex and appeared to be maintained throughout the endocytic pathway. The CLIP in Ii was not required for FcRn-Ii association. The interaction was detected in IFN--treated THP-1, epithelial and endothelial cells, and immature mouse DCs. A truncated FcRn without the cytoplasmic tail was unable to traffic to early endosomes; however, its location in early endosomes was restored by Ii expression. FcRn was detected in the late endosome/lysosome only in the presence of Ii or upon exposure to IFN-. In immature human or mouse DCs, FcRn was barely detected in the late endosome/lysosome in the absence of Ii. Taken together, the intracellular trafficking of FcRn is regulated by its intrinsic sorting information and/or Ii chain.

Vaccine strategies to prevent invasive mucosal pathogens are being sought due to the fact that 90% of infectious diseases are initiated at mucosal surfaces. However, our ability to deliver an mucosal vaccine antigen for induction of the protective immunity is limited. FcRn mediates the transport of IgG across polarized epithelial cells. Taking advantage of this unique transfer pathway, I sought to delivery of antigens across mucosal barrier using IgG Fc fused proteins. It was demonstrated that intranasal immunization with a model antigen herpes simplex virus type-2 (HSV-2) glycoprotein gD fused with an IgG Fc fragment combination with CpG ODN adjuvant resulted in a complete protection of wild type, but not FcRn knockout mice that were intravaginally challenged with virulent HSV-2 186. The immunization induced efficient mucosal and systemic antibody as well as long lasting memory immune responses. These results are the first to demonstrate that the FcRn-IgG transcellular pathway may represent a novel mucosal vaccine delivery path against mucosal infections.