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Review
. 2015 Jan;125(1):75-84.
doi: 10.1172/JCI73945. Epub 2015 Jan 2.

Immunologic manifestations of autophagy

Vojo Deretic, Tomonori Kimura, Graham Timmins, Pope Moseley, Santosh Chauhan, Michael Mandell
Review

Immunologic manifestations of autophagy

Vojo Deretic et al. J Clin Invest. 2015 Jan.

Abstract

The broad immunologic roles of autophagy span innate and adaptive immunity and are often manifested in inflammatory diseases. The immune effects of autophagy partially overlap with its roles in metabolism and cytoplasmic quality control but typically expand further afield to encompass unique immunologic adaptations. One of the best-appreciated manifestations of autophagy is protection against microbial invasion, but this is by no means limited to direct elimination of intracellular pathogens and includes a stratified array of nearly all principal immunologic processes. This Review summarizes the broad immunologic roles of autophagy. Furthermore, it uses the autophagic control of Mycobacterium tuberculosis as a paradigm to illustrate the breadth and complexity of the immune effects of autophagy.

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Figures

Figure 3
Figure 3. A spectrum of autophagic processes governs elimination of intracellular microbes.
Extracellular bacteria (pink) can induce autophagy by stimulating TLRs (i) or NODs (ii) upon shedding of PAMPs or during phagocytosis (iii). The latter induces a hybrid process termed LAP. Intracellular bacteria can be eliminated through canonical autophagy sponsored by SLRs. Some SLRs can recognize galectins (Gal) bound to β-galactoside glycans on pathogen-associated damaged vacuolar membranes (iv), whereas all SLRs identified thus far recognize ubiquitin (Ubq) on cytosolic bacteria or associated host molecules (v). A viral core can be recognized by TRIMs, which act as receptors and inducers of autophagy, thus helping to eliminate retroviral material en route to the nucleus (vi). Fusion with lysosomes leads to formation of autolysosomes (from canonical autophagy acting on cytosolic targets) or autophagolysosomes (from LAP phagosomes or from damaged conventional phagosomes). Elimination of many pathogens involves not one but a spectrum of autophagic processes (processes i–vi correspond to the above descriptions): AP, autophagy; X1, xenophagy mixed with autophagy of host membranes; X2, xenophagy of microbes only; HSX, highly selective xenophagy.
Figure 2
Figure 2. Autophagy affects lymphocyte development and function.
Autophagy affects self-renewal of HSCs, plasma cell survival, IgG secretion, survival of a special type of B cell, B1, and maintenance of memory B cells (not shown). Autophagy affects T cell survival following TCR activation and controls stability of immunologic synapses; it also controls innate immune cell (e.g., macrophage) signaling by suppressing ROS via the removal of depolarized mitochondria and inhibition of IL-1 release that influences, along with the durability of immunologic synapses, polarization of T cells into a Th17 phenotype. Autophagy also affects selection of naive T cell repertoire in the thymus by self antigen processing and presentation and survival and functionality of maturing T cells by trimming mitochondria and ER, thus ensuring Ca2+ homeostasis. Red crescents symbolize the entire autophagy pathway.
Figure 1
Figure 1. Autophagy modulates inflammation.
(A) Autophagy — a simplified pathway. TOR, AMPK, and immune signaling control activation of ULK1 and beclin 1, the central regulators of autophagy, which in turn bring about autophagic membrane formation (crescent represents a nascent phagophore) from ER with contributions from endosomes and lipid droplets (LD). Completed autophagosomes (double membrane) fuse with lysosomes to form autolysosomes or autophagolysosomes, as described in the text. (B) Autophagy promotes delivery of PAMPs and activation of endosomal TLRs (TLR7 and TLR9) and assists the unconventional secretion of IL-1β upon inflammasome activation. (C) Autophagy inhibits spurious or excessive inflammasome activation and interferes (directly or indirectly) with signaling via cGAS (generating cGAMP upon dsDNA binding), MAVS, and RIG-I to downregulate type I IFN responses, and can suppress NF-κB activation.
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