The unfolded-protein-response sensor IRE-1α regulates the function of CD8α+ dendritic cells

Fabiola Osorio; Simon J Tavernier; Eik Hoffmann; Yvan Saeys; Liesbet Martens; Jessica Vetters; Iris Delrue; Riet De Rycke; Eef Parthoens; Philippe Pouliot; Takao Iwawaki; Sophie Janssens; Bart N Lambrecht

doi:10.1038/ni.2808

The unfolded-protein-response sensor IRE-1α regulates the function of CD8α+ dendritic cells

Nat Immunol. 2014 Mar;15(3):248-57. doi: 10.1038/ni.2808. Epub 2014 Jan 19.

Authors

Affiliations

¹ 1] Unit Immunoregulation and Mucosal Immunology, VIB Inflammation Research Center, Ghent, Belgium. [2] GROUP-ID Consortium, Ghent University and University Hospital, Ghent, Belgium. [3] Department of Respiratory Medicine, Ghent University, Ghent, Belgium. [4].
² 1] GROUP-ID Consortium, Ghent University and University Hospital, Ghent, Belgium. [2] Unit of Molecular Signal Transduction in Inflammation, VIB Inflammation Research Center, Ghent, Belgium.
³ 1] Unit Immunoregulation and Mucosal Immunology, VIB Inflammation Research Center, Ghent, Belgium. [2] GROUP-ID Consortium, Ghent University and University Hospital, Ghent, Belgium. [3] Department of Respiratory Medicine, Ghent University, Ghent, Belgium.
⁴ Microscopy Core Facility, VIB Inflammation Research Center, Ghent, Belgium.
⁵ Advanced Scientific Research Leaders Development Unit, Gunma University, Gunma, Japan.
⁶ 1] Unit Immunoregulation and Mucosal Immunology, VIB Inflammation Research Center, Ghent, Belgium. [2] GROUP-ID Consortium, Ghent University and University Hospital, Ghent, Belgium. [3] Department of Respiratory Medicine, Ghent University, Ghent, Belgium. [4] Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands. [5].

PMID: 24441789
DOI: 10.1038/ni.2808

Abstract

The role of the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress in homeostasis of the immune system is incompletely understood. Here we found that dendritic cells (DCs) constitutively activated the UPR sensor IRE-1α and its target, the transcription factor XBP-1, in the absence of ER stress. Loss of XBP-1 in CD11c+ cells led to defects in phenotype, ER homeostasis and antigen presentation by CD8α+ conventional DCs, yet the closely related CD11b+ DCs were unaffected. Whereas the dysregulated ER in XBP-1-deficient DCs resulted from loss of XBP-1 transcriptional activity, the phenotypic and functional defects resulted from regulated IRE-1α-dependent degradation (RIDD) of mRNAs, including those encoding CD18 integrins and components of the major histocompatibility complex (MHC) class I machinery. Thus, a precisely regulated feedback circuit involving IRE-1α and XBP-1 controls the homeostasis of CD8α+ conventional DCs.

MeSH terms

Animals
Antigen Presentation / immunology
CD8 Antigens / immunology
CD8 Antigens / metabolism
Cross-Priming / immunology*
DNA-Binding Proteins / immunology*
DNA-Binding Proteins / metabolism
Dendritic Cells / immunology*
Dendritic Cells / metabolism
Endoplasmic Reticulum / immunology
Endoribonucleases / immunology*
Endoribonucleases / metabolism
Feedback, Physiological / physiology
Homeostasis / immunology
Immunoblotting
Immunohistochemistry
Mice
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Electron
Oligonucleotide Array Sequence Analysis
Protein Serine-Threonine Kinases / immunology*
Protein Serine-Threonine Kinases / metabolism
Protein Unfolding*
Regulatory Factor X Transcription Factors
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors / immunology*
Transcription Factors / metabolism
Unfolded Protein Response / immunology*
X-Box Binding Protein 1

Substances

CD8 Antigens
CD8alpha antigen
DNA-Binding Proteins
Regulatory Factor X Transcription Factors
Transcription Factors
X-Box Binding Protein 1
Xbp1 protein, mouse
Ern1 protein, mouse
Protein Serine-Threonine Kinases
Endoribonucleases

Associated data

GEO/GSE52857