The Role of FcRn in Antigen Presentation

Abstract

Immunoglobulins are unique molecules capable of simultaneously recognizing a diverse array of antigens and themselves being recognized by a broad array of receptors. The abundance specifically of the IgG subclass and the variety of signaling receptors to which it binds render this an important immunomodulatory molecule. In addition to the classical Fcγ receptors that bind IgG at the cell surface, the neonatal Fc receptor (FcRn) is a lifelong resident of the endolysosomal system of most hematopoietic cells where it determines the intracellular fate of both IgG and IgG-containing immune complexes (IgG IC). Cross-linking of FcRn by multivalent IgG IC within antigen presenting cells such as dendritic cells initiates specific mechanisms that result in trafficking of the antigen-bearing IgG IC into compartments from which the antigen can successfully be processed into peptide epitopes compatible with loading onto both major histocompatibility complex class I and II molecules. In turn, this enables the synchronous activation of both CD4(+) and CD8(+) T cell responses against the cognate antigen, thereby bridging the gap between the humoral and cellular branches of the adaptive immune response. Critically, FcRn-driven T cell priming is efficient at very low doses of antigen due to the exquisite sensitivity of the IgG-mediated antigen delivery system through which it operates. FcRn-mediated antigen presentation has important consequences in tissue compartments replete with IgG and serves not only to determine homeostatic immune activation at a variety of sites but also to induce inflammatory responses upon exposure to antigens perceived as foreign. Therapeutically targeting the pathway by which FcRn enables T cell activation in response to IgG IC is thus a highly attractive prospect not only for the treatment of diseases that are driven by immune complexes but also for manipulating local immune responses against defined antigens such as those present during infections and cancer.

Keywords: FcRn; IgG; antigen presentation; dendritic cells; immune complex.

Figure 1

FcRn within dendritic cells enables the presentation of IgG-complexed antigens to CD4⁺ T cells and CD8⁺ T cells. Following IgG opsonization of antigens from sources such as microbes or tumors, the immune complexes (IgG IC) bind to FcγR on the surface of dendritic cells (DC). This initiates receptor-mediated endocytosis, which delivers the IgG into the endolysosomal system of compartments. As these vesicles become more acidic during their maturation due to the recruitment of the vacuolar ATPase (V-ATPase), IgG IC dissociate from FcγR and bind instead to FcRn, which enables the subsequent trafficking of the IgG IC into antigen processing pathways that promote the generation of epitopes compatible with loading onto MHC class I and MHC class II. Machinery known to be involved in the presentation of soluble antigens for MHC class I processing and presentation, such as gp91-phox, Rab27, Sec61, TAP (transporter associated with antigen processing), and the proteasome, are all preferentially recruited to the IgG IC-containing intracellular vesicles upon ligation of FcRn. Less information is available on the compartments involved in FcRn-facilitated MHC class II restricted presentation and it remains unknown whether this occurs within the same intracellular compartment as MHC class I-restricted processing. Once at the surface, these peptide loaded MHC molecules are then able to prime CD8⁺ and CD4⁺ T cells, respectively. Furthermore, ligation of FcRn by IgG IC induces the production of IL-12 by the DC. The secreted IL-12 acts upon the primed CD4⁺ T cells to induce Th1 polarization and upon the CD8⁺ T cells to promote activation and cytotoxicity. FcRn within DC thus contributes to the activation of cell-mediated adaptive immune responses that contribute to pathogen eradication and tumor protection.