**Background:** Autophagy is a highly conserved cellular process that degrades intracellular cargo via lysosomes, maintaining homeostasis and responding to stimuli like nutrient starvation and microbial infection. This review explores the extensive interplay between autophagy and the immune system, focusing on how autophagy shapes inflammatory responses, innate immune signaling, cell-autonomous defense, and adaptive immunity. It also discusses non-canonical autophagy and the role of autophagy in infectious, metabolic, and autoimmune diseases.
**Methods:** This is a narrative review that synthesizes findings from numerous primary research studies. The authors systematically examine the interactions between autophagy and various pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), C-type lectin receptors (CLRs), and the cGAS-STING pathway. They also review the roles of interferon-inducible GTPases (IRGs and GBPs), complement proteins, and the impact of autophagy on MHC class I and II antigen presentation, T lymphocyte biology, and non-canonical autophagy pathways such as LC3-associated phagocytosis (LAP). The review integrates evidence from in vitro studies, animal models, and human genetic associations.
**Key Results:** The review presents several key findings: (1) Multiple TLRs (e.g., TLR2, TLR4, TLR7) activate autophagy through MyD88 and TRIF pathways, while autophagy also degrades TLR signaling components like TRIF to limit inflammation. (2) NOD1 and NOD2 induce xenophagy via ATG16L1 and IRGM, and Crohn's disease-associated mutations in NOD2 and ATG16L1 impair this function. (3) Autophagy suppresses inflammasome activation by degrading NLRP3, ASC, and pro-IL-1β, and by removing damaged mitochondria. For example, loss of ATG16L1 in mouse macrophages leads to excessive IL-1β and IL-18 production. (4) The cGAS-STING pathway induces autophagy, and STING itself is degraded by p62/SQSTM1-dependent autophagy to maintain immune homeostasis. (5) Interferon-inducible GTPases (IRGs and GBPs) cooperate with non-canonical autophagy to target pathogen-containing vacuoles, such as those of Toxoplasma gondii, for destruction. In mice, Irgb6 recognizes phospholipids on the parasitophorous vacuole, leading to vesiculation and parasite death. (6) Autophagy influences adaptive immunity by promoting MHC class II presentation of endogenous antigens in thymic epithelial cells, affecting T cell selection, and by regulating MHC class I expression and cross-presentation. (7) In T lymphocytes, autophagy is critical for development, survival, and effector function; for instance, ATG7 deficiency impairs memory CD8 T cell formation. (8) Non-canonical autophagy (LAP) facilitates phagosome maturation and degradation of pathogens and dead cells, limiting inflammation. LAP-deficient animals develop a lupus-like phenotype upon repeated injection of dead cells. (9) Autophagy dysregulation is linked to numerous diseases: ATG16L1 T300A variant is associated with Crohn's disease and aberrant Paneth cells; autophagy deficiency in macrophages exacerbates colitis, obesity-induced inflammation, and atherosclerosis; and impaired autophagy in neurons contributes to neurodegenerative diseases.
**Clinical Implications:** The review underscores that autophagy is a central regulator of immune responses, with both protective and pathogenic roles depending on context. Targeting autophagy pathways offers therapeutic potential for inflammatory bowel disease, infections (e.g., Mycobacterium tuberculosis, SARS-CoV-2), autoimmune diseases (e.g., systemic lupus erythematosus, multiple sclerosis), and metabolic disorders. Pharmacological modulators such as rapamycin (mTOR inhibitor), metformin (AMPK activator), and vitamin D have shown efficacy in preclinical models. However, the complexity of autophagy-immune crosstalk necessitates careful targeting to avoid adverse effects, as autophagy can both suppress and promote inflammation depending on the disease stage and cell type.