Intracellular trafficking of class I MHC: Transport through the endocytic route

Abstract

Major histocompatibility complex (MHC) class I molecules can present antigenic peptides to CD8+ T cells, a process pivotal for anti-tumor and anti-viral immunity. Newly synthesized class I MHC is assembled in the ER and transported to the cell surface, only when stably complexed with high-affinity peptide. At the plasma membrane, an equilibrium in surface expression of class I MHC is maintained through continuous internalization and recycling. Class I MHC can be internalized in at least two distinct manners. Once internalized, class I MHC molecules access the endocytic route and can be recycled to the plasma membrane from the juxtanuclear located endocytic recycling compartment (ERC) or progress to lysosomes for eventual degradation. Class I MHC returns to the plasma membrane from the ERC via membranous tubules. Tubular transport of class I MHC seems to be regulated by a complex machinery involving players such as the small GTPase Arf6, the EH-domain containing protein EHD1 and distinct Rab proteins. Besides the classical pathway of endogenous peptide presentation on class I MHC, exogenous peptide can also be presented on class I MHC in a process termed ‘cross-presentation’. Dendritic cells (DCs) are especially potent cross-presenting cells. In DCs, class I MHC in late endosomal compartments colocalizes with class II MHC molecules that present antigenic peptides to CD4+ T cells. Upon inducing DC maturation, class I and class II MHC can be recruited to the cell surface via membranous tubules that are clearly distinct from the recycling tubules extending from the ERC. Both tubular transport compartments are aligned along microtubules and can likely be directed towards an interacting T cell. Class I MHC loading with exogenous peptide for cross-presentation can likely occur at diverse endosomal compartments, as long as the proteolytic environment is favorable and peptide-exchange on class I MHC can take place. Recycling of class I MHC from both the early endosomal ERC and lysosomes could facilitate cross-presentation.