Study of cellular distribution and biological functions of neonatal Fc receptor in immune cells

Immunoglobulin G (IgG) is the major class of immunoglobulins and the protein with the longest serum half-life. IgG is also actively transferred to the fetus, giving the full-term fetus IgG levels over maternal levels and protective immunity. The MHC class I related neonatal Fc receptor (FcRn) is responsible for both prenatal trans-epithelial IgG transport and protection from catabolism. Recently, it is shown that FcRn is also expressed in human monocytes, macrophages and dendritic cells (DC). However, the biological functions of FcRn in these immune cells are unknown. Since the major function of DC is antigen presentation and FcRn is shown to transport IgG-bound antigen across epithelial barriers for presentation, we hypothesize that FcRn in DC may functi on as an antigen receptor, enhancing the uptake and presentation of IgG-antigen complexes. The principal objective is to identify biological functions of FcRn in professional antigen presenting cells (APC) such as DC. First, confocal imaging experiments w ill show whether FcRn traffics to the endosomal-lysosomal compartments where antigen processing and binding occurs. Next, in vitro functional studies using WT or FcRn-/- DC presenting Fc containing antigens to T cells will show whether FcRn in DC is invol ved in antigen presentation. In parallel, we will generate FcRn-/- and WT bone marrow chimeric mice and study steady-state IgG levels, specific IgG responses and in vivo T cell proliferation after immunization with Fc-containing antigen. These experiments will delineate the biological function of FcRn in hematopoietic cells which is so far entirely unknown. Finally, we will investigate the clinical relevance of FcRn by studying the role of FcRn in presentation of gluten antigen in celiac specimens ex vivo . Overall, these studies may give new insights into the diversified biological functions of FcRn, possibly identifying new FcRn function and thus making FcRn the 4th Fc receptor involved in antigen uptake in APC.