Yonsei Med J.  2012 Mar;53(2):241-247. 10.3349/ymj.2012.53.2.241.

Autophagy in Innate Recognition of Pathogens and Adaptive Immunity

• Oh JE
• Lee HK

• KMID: 1120188
• DOI: http://doi.org/10.3349/ymj.2012.53.2.241

Abstract

Autophagy is a specialized cellular pathway involved in maintaining homeostasis by degrading long-lived cellular proteins and organelles. Recent studies have demonstrated that autophagy is utilized by immune systems to protect host cells from invading pathogens and regulate uncontrolled immune responses. During pathogen recognition, induction of autophagy by pattern recognition receptors leads to the promotion or inhibition of consequent signaling pathways. Furthermore, autophagy plays a role in the delivery of pathogen signatures in order to promote the recognition thereof by pattern recognition receptors. In addition to innate recognition, autophagy has been shown to facilitate MHC class II presentation of intracellular antigens to activate CD4 T cells. In this review, we describe the roles of autophagy in innate recognition of pathogens and adaptive immunity, such as antigen presentation, as well as the clinical relevance of autophagy in the treatment of human diseases.

Keyword

Autophagy; pathogen recognition; pattern recognition receptors; antigen presentation

MeSH Terms

Adaptive Immunity/immunology/*physiology
Animals
Antigen Presentation/immunology/physiology
Autophagy/immunology/*physiology
Humans
Major Histocompatibility Complex/immunology/physiology

Figure

• 

  Fig. 1 Autophagy contributes to innate and adaptive immune responses against pathogens. (A) TLR promotes the induction of autophagy for pathogen elimination. TLR4 signaling via the TRIF-p38 axis, but not via MyD88, induces the formation of autophagosome and subsequent elimination of Mycobacteria bacilli. TLR7 signaling induced by two different ligands, single-stranded RNA and imiquimod, induces the formation of an autophagosome to eliminate Bacillus Calmette-Guerin. Atgs, such as Atg5, beclin and PI3K, are required for the formation of autophagosomes via TLR stimulation. In another case, Atg facilitates the TLR-dependent elimination of pathogens by promoting phagosome maturation. When zymosan (a particle of fungal cell walls) is phagocytosed, TLR2 induces the recruitment of LC3 to the phagosomal membrane, leading to the maturation of phagosomes and elimination of the fungus. This process depends on Atg5 and Atg7. (B) Autophagy supports antiviral responses by promoting viral sensing. In pDCs, autophagy mediates the recognition of the virus infection by delivering viral replication intermediates in the cytosol to lysosomes, where TLR recognition occurs. However, in non-pDCs, autophagy negatively regulates antiviral type I IFN responses. The Atg5-Agt12 conjugate directly associates with CARD domains of RIG-I, a cytosolic receptor for viral nucleic acids, and IPS-1, suppressing type I IFN production. Consequently in Atg5-deficient MEFs, RLR signaling results in overproduction of type I IFNs and resistance to VSV infection. In cases of dsDNA recognition, STING, a multispanning membrane protein, is translocated from the ER to the Golgi apparatus and assembled with TBK1, which phosphorylates the transcription factor IRF3, resulting in the production of type I IFN. Atg9a, an essential component of autophagy, is co-localized with STING in the Golgi apparatus and controls the dynamic translocation of STING and assembly with TBK1. In Atg9a-deficient MEFs, the translocation of STING from the Golgi apparatus to the cytoplasmic punctate structures and assembly with TBK1 are greatly enhanced, which, in turn, induces aberrant activation of type I IFN responses. (C) Atg16L1 regulates endotoxin-induced inflammasome activation. In autophagy-deficient cells, IL-1β and IL-18 production is enhanced in response to LPS. Macrophages lacking Atg16L1 induce high-levels of ROS, which, in turn, activates caspase-1, leading to the processing of IL-1β. However, in macrophages of wild-type mice, generation of ROS is inhibited by autophagy-related protein, leading to limited production of IL-1β. (D) Autophagy is involved in MHC class II processing and presentation of intracellular antigens to CD4 T cells. Intracellular antigens are engulfed by autophagosomes, transported to MHC class II loading compartments (MIIC), and then loaded onto MHC class II molecules for presentation to CD4 T cells. TLR, toll-like receptor; Atg, autophagy-related genes; pDCs, plasmacytoid dendritic cells; CARD, caspase recruitment domain; RIG-I, retinoic acid inducible gene I; MEFs, mouse embryonic fibroblasts; RLR, RIG-I-like receptor; VSV, vesicular stomatitis virus; STING, stimulator of IFN genes; TBK1, TANK-binding kinase 1; LPS, lipopolysaccharides; ROS, reactive oxygen species; TRIF, TIR domain-containing adapter-inducing interferon-β; IFN, interferon; IPS-1, IFN-β promoter stimulator-1; ER, endoplasmic reticulum; IRF, interferon regulatory factor; IL, interleukin; MHC, major histocompatibility complex.

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