The MHC Class II-Associated Invariant Chain Interacts with the Neonatal Fcγ Receptor and Modulates Its Trafficking to Endosomal/Lysosomal Compartments

Abstract

The neonatal Fc receptor for IgG (FcRn) transfers maternal IgG to the offspring and protects IgG from degradation. The FcRn resides in an acidic intracellular compartment, allowing it to bind IgG. In this study, we found the association of FcRn and invariant chain (Ii). The interaction was initiated within the endoplasmic reticulum by Ii binding to either the FcRn H chain alone or FcRn H chain-β2-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 also detected in IFN-γ-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 also detected in the late endosome/lysosome only in the presence of Ii or on exposure to IFN-γ. In immature human or mouse DCs, FcRn was barely detected in the late endosome/lysosome in the absence of Ii. Furthermore, the cytoplasmic tail of Ii conferred tailless FcRn to route to both the early endosome and late endosome/lysosome in a hybrid molecule. Because the FcRn is expressed in macrophages and DCs or epithelial and endothelial cells where Ii is induced under inflammation and infection, these results reveal the complexity of FcRn trafficking in which Ii is capable of expanding the boundary of FcRn trafficking. Taken together, the intracellular trafficking of FcRn is regulated by its intrinsic sorting information and/or an interaction with Ii chain.

The invariant chain transports TNF family member CD70 to MHC class II compartments in dendritic cells

“…This may occur directly from the trans-Golgi network, but can also involve routing via the plasma membrane (Bénaroch et al, 1995;McCormick et al, 2005;Dugast et al, 2005). Ii also performs such a chaperone function for CD1d (Kang and Cresswell, 2002;Jayawardena-Wolf et al, 2001) and for the neonatal Fc receptor (Ye et al, 2008), both of which are closely related to MHC molecules. A chaperone function of Ii for CD70 is unusual in this context, because the structure of TNF family members is distinct from that of MHC-like molecules (Banner et al, 1993).…”

The Neonatal FcR-Mediated Presentation of Immune-Complexed Antigen Is Associated with Endosomal and Phagosomal pH and Antigen Stability in Macrophages and Dendritic Cells

“…The anti-EEA1 mAb and rat anti-mouse transferrin receptor (TFR) Ab were obtained from BD Biosciences. Preparation of the affinity-purified rabbit anti-mouse FcRn Ab has been described (12). All fluorescence-conjugated secondary Abs were purchased from Invitrogen.…”

“…In an acidic compartment (e.g., in early endosomes), FcRn binds to IgG and causes it to be recycled back to cell surface (11). Interestingly, FcRn may appear in the lysosome through its interactions with the MHC class II-associated Ii chain (12) or with internalized multimeric IgG-Ag complexes (13); it may also appear in the phagosomal compartment of neutrophils (14). Depending on the pH of its environment, FcRn either binds preferentially with IgG or albumin (pH # 6.5) or releases it (pH 7.0-7.4) (8)(9)(10).…”

A Neonatal Fc Receptor-Targeted Mucosal Vaccine Strategy Effectively Induces HIV-1 Antigen-Specific Immunity to Genital Infection

“…Immunohistochemical staining of mouse FcRn was performed using an affinity-purified rabbit anti-mouse FcRn antibody (51). Briefly, the lungs and trachea were excised and embedded in Tissue-Tek OCT compound (Miles, Elkhart, IN).…”

“…All cells were maintained in a humidified atmosphere of 5% CO 2 at 37°C. Affinity-purified antibody for mouse FcRn was produced as previously described (51). Purified mouse IgG and chicken IgY were from Rockland Laboratories (Gilbertsville, PA).…”