Macropinocytosis in phagocytes: regulation of MHC class-II-restricted antigen presentation in dendritic cells

Abstract

Dendritic cells (DCs) are outstanding antigen presenting cells (APCs) due to their robust ability to internalize extracellular antigens using endocytic processes such as receptor-mediated endocytosis, phagocytosis, and macropinocytosis. Macropinocytosis mediates the non-specific uptake of soluble antigens and occurs in DCs constitutively. Macropinocytosis plays a key role in DC-mediated antigen presentation to T cells against pathogens and the efficiency of macropinocytosis in antigen capture is regulated during the process of DC maturation. Here, we review the methods to study macropinocytosis, describe our current knowledge of the regulatory mechanisms of antigen uptake via macropinocytosis and the intracellular trafficking route followed by macropinocytosed antigens, and discuss the significance of macropinocytosis for DC function.

Keywords: MHC class II; antigen presentation; dendritic cell; endocytosis; macropinocytosis.

Figure 1

Pathways of Exogenous Antigen Uptake in DCs. DCs internalize extracellular antigens using three main endocytic pathways. Phagocytosis is an endocytic process in which opsonized particles bind to specific receptors on the DC surface and enter cells in membrane-derived phagosomes. Phagocytosed antigens (Blue) can fuse with MHC-II⁺ lysosomes to generate phagolysosomes (not shown) or can be directly targeted into late endosomal/lysosomal antigen processing compartments to generate pMHC-II complexes. Macropinocytosis mediates non-specific uptake of soluble antigens into the cell via macropinosomes. Antigens in macropinosomes (Red) are transferred into early endosomes that eventually fuse with multivesicular late endosomal/lysosomal antigen processing compartments. Macropinocytosed antigens are degraded and loaded on MHC-II in these compartments. Receptor-mediated endocytosis is a process in which small soluble antigens bind to specific receptors on the DC surface that internalize in clathrin-coated vesicles or in clathrin-uncoated vesicles (not shown). Following uncoating of clathrin, antigens in clathrin-coated vesicles (Purple) are delivered to early endosomes and eventually to antigen processing compartments for proteolytic degradation and pMHC-II formation. After formation in antigen processing compartments, pMHC-II complexes traffic to plasma membrane to initiate antigen-specific adaptive immune responses.