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.

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 Unfolding*
  • Protein-Serine-Threonine Kinases / immunology*
  • Protein-Serine-Threonine Kinases / metabolism
  • 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