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Autophagy in the renewal, differentiation and homeostasis of immune cells

Nature Reviews Immunology (2018) | Download Citation

Abstract

Across all branches of the immune system, the process of autophagy is fundamentally important in cellular development, function and homeostasis. Strikingly, this evolutionarily ancient pathway for intracellular recycling has been adapted to enable a high degree of functional complexity and specialization. However, although the requirement for autophagy in normal immune cell function is clear, the mechanisms involved are much less so and encompass control of metabolism, selective degradation of substrates and organelles and participation in cell survival decisions. We review here the crucial functions of autophagy in controlling the differentiation and homeostasis of multiple immune cell types and discuss the potential mechanisms involved.

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Acknowledgements

A.J.C. and A.K.S. are both funded by the Wellcome Trust (104549/Z/14/Z to A.J.C. and 103830/Z/14/Z to A.K.S.).

Reviewer information

Nature Reviews Immunology thanks F. Gros, J. Martinez and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Affiliations

  1. Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford, UK

    • Alexander J. Clarke
    •  & Anna Katharina Simon

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Both authors wrote and edited the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Anna Katharina Simon.

Glossary

Oxidative phosphorylation

(OXPHOS). The production of ATP through the oxidation of nutrients. The electron transport chain in mitochondria produces an electrochemical gradient that is used to make ATP.

Tricarboxylic acid cycle

(TCA cycle). A metabolic pathway that oxidizes acetyl-CoA derived from pyruvate to release stored energy in the form of NADH, which then enters oxidative phosphorylation. The TCA cycle is crucial for carbohydrate, protein and lipid metabolism.

Autophagy genes

Genes related to autophagy. The core machinery of autophagy is encoded by ~30 genes. The most commonly deleted genes in experimental settings include Ulk1, Ulk2, Atg3, Atg5, Becn1, Atg7 and Atg16l1, which are all essential for autophagy.

β-Oxidation

The catabolism of fatty acid molecules to produce acetyl-CoA.

LC3-associated phagocytosis

(LAP). A form of non-canonical autophagy in which LC3 is conjugated to the phagosomal membrane using some components of the autophagy pathway.

Unc51-like autophagy-activating kinase 1 complex

(ULK1 complex). The major complex controlling the initiation of autophagy, which is targeted by mechanistic target of rapamycin complex 1 (mTORC1) and 5′-AMP-activated protein kinase (AMPK).

Mechanistic target of rapamycin complex 1

(mTORC1). A complex — which consists of mTOR together with the protein raptor — that senses nutrient status and is a master regulator of protein synthesis and cell growth.

M1 macrophages and M2 macrophages

‘M1’ and ‘M2’ are classifications historically used to define macrophages activated in vitro as pro-inflammatory (when ‘classically’ activated with IFNγ and lipopolysaccharide) or anti-inflammatory (when ‘alternatively’ activated with IL-4 or IL-10), respectively. However, in vivo macrophages are highly specialized, transcriptomically dynamic and extremely heterogeneous with regard to their phenotypes and functions, which are continuously shaped by their tissue microenvironment. Therefore, the M1 or M2 classification is too simplistic to explain the true nature of in vivo macrophages, although these terms are still often used to indicate whether the macrophages in question are more pro- or anti-inflammatory.

Senescence

A process that typically occurs in aged cells. It involves the acquisition of progressive and diverse cellular phenotypes including growth arrest, telomere attrition, damaged macromolecules and the secretion of cytokines, chemokines and proteases with pro-inflammatory properties (the senescence-associated secretory phenotype), which together lead to tissue dysfunction.

Non-classical cross-presentation

The presentation of endogenous proteins, which enter the endosomal pathway, on MHC class II molecules by antigen-presenting cells.

Antibody affinity maturation

The progressive increase in antibody affinity that occurs during the immune response as the germinal centre reaction selects for B cells producing higher-affinity immunoglobulin.

Unfolded protein response

The stress response pathway that is activated by the accumulation of unfolded or defective proteins in the endoplasmic reticulum.

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DOI

https://doi.org/10.1038/s41577-018-0095-2