The goal of this proposal is to elucidate the cell biology of FcRn-mediated IgG transcytosis across the intestinal epithelial barrier. FcRn was first identified as the receptor for IgG in the neonatal rodent intestine responsible for passive transmission of maternal IgG to the newborn. Although passive acquisition of IgG in humans does not depend on intestinal IgG transport, we have recently observed expression of FcRn beyond neonatal life in the adult human intestine and in the polarized human intestinal epithelial cell line, T84. Using T84 cells as a model epithelium, we have demonstrated FcR-dependent bidirectional transcytosis of IgG across confluent, polarized T84 cell monolayers. These data raise the distinct possibility that FcRn-mediated transport of IgG occurs by direct transcytosis across the polarized intestinal epithelium. Thus, studies proposed in this grant application will address our central hypothesis that FcRn mediates the transport of IgG via direct transcytosis across the polarized intestinal epithelium. In studies proposed in this application, we will: 1) Elucidate the cell biology of FcRn-mediated IgG transcytosis in polarized T84 cells and 2) Determine whether the extracellular, transmembrane, and/or lumenal domains of FcRn heavy chain contain structural motifs which govern biogenesis, steady-state distribution, recycling, and transcytosis.
