A Central Role for Atg5 in Microbiota-Dependent Foxp3+ RORγt+ Treg Cell Preservation to Maintain Intestinal Immune Homeostasis.

Carlos Plaza-Sirvent,Marina C Pils,Alisha W Bronietzki,Bei Zhao,Marc Schuster,Till Strowig,Ingo Schmitz,Neda Tafrishi

doi:10.3389/fimmu.2021.705436

Abstract

Autophagy is an evolutionary conserved catabolic pathway that ensures the degradation of intracellular components. The autophagic pathway is regulated by autophagy-related (Atg) proteins that govern formation of double-membraned vesicles called autophagosomes. Autophagy deficiency in regulatory T (Treg) cells leads to increased apoptosis of these cells and to the development of autoimmune disorders, predominantly characterized by intestinal inflammation. Recently, RORγt-expressing Treg cells have been identified as key regulators of gut homeostasis, preventing intestinal immunopathology. To study the role of autophagy in RORγt+ Foxp3+ Treg cells, we generated mice lacking the essential component of the core autophagy machinery Atg5 in Foxp3+ cells. Atg5 deficiency in Treg cells led to a predominant intestinal inflammation. While Atg5-deficient Treg cells were reduced in peripheral lymphoid organs, the intestinal RORγt+ Foxp3+ subpopulation of Treg cells was most severely affected. Our data indicated that autophagy is essential to maintain the intestinal RORγt+ Foxp3+ Treg population, thereby protecting the mice from gut inflammatory disorders.

Highlights

IntroductionMacroautophagy (hereafter called autophagy) is an ancient catabolic process that degrades bulky cargo via the lysosomal pathway
Macroautophagy is an ancient catabolic process that degrades bulky cargo via the lysosomal pathway
Our study shows the particular requirement of autophagy for the maintenance of the RORgt+ Foxp3+ Treg cells, which are essential for sustaining intestinal homeostasis

Summary

Introduction

Macroautophagy (hereafter called autophagy) is an ancient catabolic process that degrades bulky cargo via the lysosomal pathway. The cargo to be degraded may comprise protein aggregates, cell organelles or intracellular pathogens and is enclosed in double membraned vesicles, called autophagosomes [1]. At the core of the autophagic machinery are two ubiquitinlike conjugation systems, in which first the ubiquitin-like molecule ATG12 is conjugated to ATG5 [2]. Together with ATG16L1, the ATG5-12 complex associates with nascent autophagosomes and acts as Autophagy Preserves Foxp3+ RORgt+ Tregs an E3 ligase to conjugate the ubiquitin-like molecule ATG8 to the lipid phosphatidylethanolamine [3]. The ATG family of proteins is crucial for elongation of the nascent autophagosome and closure of the double membrane vesicle, which fuses with a lysosome to degrade the cargo [4]

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