Unveiling the roles of autophagy in innate and adaptive immunity

Abstract

Cells digest portions of their interiors in a process known as autophagy to recycle nutrients, remodel and dispose of unwanted cytoplasmic constituents. This ancient pathway, conserved from yeast to humans, is now emerging as a central player in the immunological control of bacterial, parasitic and viral infections. The process of autophagy may degrade intracellular pathogens, deliver endogenous antigens to MHC-class-II-loading compartments, direct viral nucleic acids to Toll-like receptors and regulate T-cell homeostasis. This Review describes the mechanisms of autophagy and highlights recent advances relevant to the role of autophagy in innate and adaptive immunity.

Figure 1. Cellular events in autophagy.

The cellular events during digestion of self constituents or intracellular pathogens follow three distinct stages: initiation (formation of the phagophore), elongation (growth and closure) and maturation of a double membrane autophagosome into an autolysosome. a | Autophagy sequesters and removes cellular constituents from the cytosol, including surplus or damaged organelles from the cytosol. b | Autophagy can eliminate bacteria (free in the cytosol or inside a phagosome), viruses and protozoan parasites in a manner similar to the elimination of self constituents.

Figure 2. Molecular events in autophagy.

Autophagy is regulated by a set of autophagy-related proteins (ATG proteins). In the absence of amino acids or in response to other stimuli, ATG1 and a complex of the class III PI3K (phosphoinositide 3-kinase) VPS34 and beclin 1 lead to the activation of downstream ATG factors that are involved in the initiation (a), elongation (b) and maturation (c) of autophagy. a | In amino-acid-rich conditions, VPS34 contributes to mTOR (mammalian target of rapamycin) activation and inhibition of ATG1 and autophagy. The sources of membrane for autophagosome initiation and elongation may include those containing the only known membrane integral ATG protein ATG9, redistributing between a resting location to autophagosomes in an ATG1- and PI3K-dependent manner. ATG9 redistribution may depend on ATG18, which binds phosphatidylinositol-3-phosphate (PtdIns3P). b | The elongation and shape of the autophagosome are controlled by two protein (and lipid) conjugation systems, similar to the ubiquitylation systems: the ATG12 and LC3 (also known as ATG8)–phosphatidylethanolamine (PE) conjugation pathways, which include E1-activating and E2-conjugating enzymes. ATG12 is initially conjugated to ATG7 (an E1-activating enzyme) and then is transferred to the E2-like conjugating enzyme ATG10. This intermediate presents ATG12 for conjugation to an ATG5 lysine residue. The ATG5–ATG12 conjugate, stabilized non-covalently by ATG16, triggers oligomerization on the outside membrane of the growing autophagosome, and enhances LC3 carboxy-terminal lipidation through the LC3 conjugation system. Upon autophagosome closure, ATG5–ATG12–ATG16 and LC3 (delipidated by ATG4) are recycled. c | LC3 associated with the lumenal membrane remains trapped in the autophagosome and is degraded during maturation into the autolysosome, which involves fusion of autophagosomes with late endosomes, including endosomal multivesicular bodies and lysosomal organelles, and dissolution of the internal membrane. VPS34 has a role in the formation of late endosomal multivesicular bodies and lysosomal organelles contributing to the maturation stages of autophagy.

Figure 3. Autophagy eliminates intracellular microorganisms.

a | Group A Streptococci captured within an autophagosome. Image kindly provided by Tamotsu Yoshimori, Osaka University, Japan. b | Mycobacterium bovis bacillus Calmette–Guérin (BCG) present in a mycobacterial autophagosome (MAP) that is fusing with a multivesicular body (MVB). Image reproduced with permission from Ref. © (2004) Cell Press. c | Herpes simplex virus type I (HSV-1) virion(s) in the process of being surrounded by an isolation membrane (left panel), engulfed inside an autophagosome (middle panel) or degraded inside an autolysosome (right panel). Image reproduced with permission from Ref. © (2006) Landes Bioscience.

Figure 4. Functions of autophagy in innate and adaptive immunity during infection with intracellular pathogens.

a | Intracellular pathogens (bacteria, parasites and viruses) that are either free inside the cytosol, inside phagosomes or inside pathogen-containing vacuoles are surrounded by isolation membranes, engulfed into autophagosomes, which fuse with lysosomes, and then degraded inside autolysosomes. b | Viral nucleic acids are transferred by autophagy from the cytoplasm to intracellular compartments containing Toll-like receptor 7 (TLR7), which signals the induction of type I interferon (IFN) production. c | Viral antigens (and potentially other endogenously synthesized microbial antigens and self antigens) are engulfed into autophagosomes that fuse with MHC-class-II-containing late endosomes (MIICs), and then loaded onto MHC class II molecules for presentation to CD4⁺ T cells. Cytosolic antigens that contain a KFERQ recognition motif may also be directly imported into MIICs by chaperone-mediated autophagy. CLIP, class II-associated invariant chain peptide.