Autophagy and Immune Tolerance.

The immune system plays a critical role in defense against invading pathogens, and its function must be strictly controlled to maintain intracellular homeostasis. Once suffering microbial invasion or receiving danger signals, the immune system initiates the responses timely. After the threat removal, the immune system should be shut down to avoid the harm caused by excessive immune activation. Additionally, the immune system needs to be internally adjusted so that it does not respond to self-antigens to avoid autoimmune diseases. The states of nonresponse in immunity are termed as immune tolerance. Numerous studies indicated that macroautophagy (hereafter named as autophagy) is involved in T cells and B cells related immune tolerance. Recently, more and more researches demonstrated that autophagy is not only capable of nonselective degradation of cellular macromolecular components but also responsible for sorting and transporting autophagic substrates through a group of cargo receptors for selective degradation, which is called as selective autophagy. Recent studies indicated that selective autophagy can effectively regulate the immune tolerance and avoid over-activation of immune response by targeting multiple receptors and effectors of immune cells. In this chapter, we will focus on how autophagy participates explicitly in the adaptive and innate immune tolerance.

The Cross-Regulation Between Autophagy and Type I Interferon Signaling in Host Defense.

The production of type I interferons (IFNs) is one of the hallmarks of intracellular antimicrobial program. Typical type I IFN response activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, which results in the transcription of plentiful IFN-stimulated genes (ISGs) to establish the comprehensive antiviral states. Type I IFN signaling should initiate timely to provoke innate and adaptive immune responses for effective elimination of the invading pathogens. Meanwhile, a precise control must come on the stage to restrain the persistent activation of type I IFN responses to avoid attendant toxicity. Autophagy, a conserved eukaryotic degradation system, mediated by a number of autophagy-related (ATG) proteins, plays an essential role in the clearance of invading microorganism and manipulation of type I responses. Autophagy modulates type I IFN responses through regulatory integration with innate immune signaling pathways, and by removing endogenous ligands of innate immune sensors. Moreover, selective autophagy governs the choice of innate immune factors as specific cargoes for degradation, thus tightly monitoring the type I IFN responses. This review will focus on the cross-regulation between autophagy and type I IFN signaling in host defense.

TRIM11 attenuates Treg cell differentiation by p62-selective autophagic degradation of AIM2.

Ubiquitination is an important protein modification that regulates diverse biological processes, including CD4+ T cell differentiation and functions. However, the function of most E3 ubiquitin ligases in CD4+ T cell differentiation and CD4+ T cell-mediated pathological diseases remains unclear. In this study, we find that tripartite motif-containing motif 11 (TRIM11) specifically negatively regulates regulatory T (Treg) cell differentiation in CD4+ T cells and promotes autoimmune disease development in an AIM2-dependent manner. Mechanistically, TRIM11 interacts with absent in melanoma 2 (AIM2) and promotes the selective autophagic degradation of AIM2 by inducing AIM2 ubiquitination and binding to p62 in CD4+ T cells. AIM2 attenuates AKT and FOXO1 phosphorylation, MYC signaling, and glycolysis, thereby promoting the stability of Treg cells during experimental autoimmune encephalomyelitis (EAE). Our findings suggest that TRIM11 serves as a potential target for immunotherapeutic intervention for dysregulated immune responses that lead to autoimmunity and cancers.