THE FUNCTIONAL REGULATION OF FCRN EXPRESSION AND FCRN-MEDIATED ANTIGEN PRESENTATION

Abstract

The neonatal Fc receptor for IgG (FcRn), a major histocompatibility complex (MHC) class I-related molecule, plays an important role in IgG transport and protection. The transport of IgG across epithelial and endothelial barriers and the IgG homeostasis maintained by FcRn contributes to the effective humoral immunity. Thus, the level of FcRn itself will affect the IgG-associated immune responses.

Although FcRn is expressed in a variety of tissues and cell types, the extent to which FcRn expression is regulated by immunological and inflammatory events remains unknown.I showed here that FcRn was up-regulated by the stimulation of inflammatory cytokines or Toll-like receptor ligands in human peripheral blood mononuclear cell (PBMC) and THP-1 cell line. By chromatin immunoprecipitation, I identified three NF-κB binding sites within introns 2 and 4 of the human FcRn gene. These intronic binding sites boost FcRn transcription activities through looping with the promoter region. In contrast, FcRn expression was down-regulated by Th1 cytokine IFN-γ, and the down-regulation of FcRn was not caused by apoptosis or the instability of FcRn mRNA. It has been demonstrated that IFN-γ activated STAT1 bound with GAS sequence in human FcRn promoter, and which blocked the transcriptional machinery.

Fc gamma receptors (FcγRs) expressed in macrophages (MФ) and dendritic cells (DCs) can mediate antigen presentation in both MHC class II and MHC class I pathways. We tested here the role for FcRn in antigen presentation of IgG-restricted Immune complexes (ICs). It was observed that the expression of FcRn in MФ, but not in DC enhanced the phagosomal ICs antigen presentation to CD4 T cells. A low pH value in phgosome of MФ facilitated FcRn binding to ICs, stabilizing the antigens and promoting the efficient MHC II-peptide assembly. However, the alkalized phagosomes in DC failed FcRn to enhance the antigen presentation of ICs.