Autophagy and its role in MHC-mediated antigen presentation

Abstract

Intracellular degradation by autophagy plays a role in the maintenance of cellular homeostasis under normal conditions and during periods of cellular stress. Autophagy has also been implicated in several other cellular processes including immune recognition and responsiveness. More specifically, autophagy has been identified as a route by which cytoplasmic and nuclear Ag are delivered to MHC class II molecules for presentation to CD4(+) T cells. Autophagy has also recently been implicated in MHC class I cross-presentation of tumor Ag and the activation of CD8(+) T cells. This review discusses the role of autophagy in modulating MHC class I and class II Ag presentation as well as its implication in regulating autoimmunity and tolerance, tumor immunity, and host defense against intracellular pathogens.

FIGURE 1. Pathways of autophagy in MHC class II-mediated Ag presentation

In macroautophagy, the cytoplasm is sequestered into double-membraned structures known as autophagosomes which fuse with lysosomes. In chaperone-mediated autophagy (CMA), specific cytosolic proteins are transported into lysosomes via a molecular chaperone/receptor complex composed of hsc70 and LAMP-2A.

FIGURE 2. Autophagy as a potential mechanism for MHC class I-mediated presentation of tumor Ag

Macroautophagy can be induced in tumor cells undergoing cellular stress as a result of nutrient depletion or chemotherapy. Autophagosomes containing tumor Ag may be released into the extracellular environment where they are internalized by DC. How and where tumor Ag in autophagosomes intersect with MHC class I molecules in DC is unknown. DC present tumor peptides in the context of class I for the activation of CD8⁺ T cells.

FIGURE 3. Autophagy pathways in the MHC class-mediated presentation of cytoplasmic and nuclear Ag

Approximately 10–25% of MHC class II molecules display peptides from nuclear and cytoplasmic Ag likely accessing autophagy to reach class II. Left, Cytoplasmic Ag are first processed by cytosolic proteases and then utilize chaperone-mediated autophagy (CMA) to access lysosomes. These antigenic fragments intersect with MHC class II molecules in a mature endosomal/lysosomal compartment known as the MIIC prior to presentation to CD4⁺ T cells. Right, Cytoplasmic or nuclear Ag are sequestered into double-membrane structures known as autophagosomes which continuously fuse with mature endsosomes such as the MIIC and lysosomes, thus allowing Ag to associate with MHC class II molecules. Further processing of the cytoplasmic or nuclear Ag by lysosomal proteases may occur prior to binding to class II and presentation to CD4⁺ T cells.