Deficiency of the intramembrane protease SPPL2a alters antimycobacterial cytokine responses of dendritic cells

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Ann Christine Gradtke - , Dresden University of Technology (Author)
  • Torben Mentrup - , Institute of Physiological Chemistry, Dresden University of Technology (Author)
  • Christian H.K. Lehmann - , Friedrich-Alexander University Erlangen-Nürnberg, Deutsches Zentrum Immuntherapie (DZI) and Medical Immunology Campus Erlangen, University Hospital at the Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Florencia Cabrera-Cabrera - , Dresden University of Technology (Author)
  • Christine Desel - , Kiel University (Author)
  • Darian Okakpu - , Institute of Physiological Chemistry, Chair of Cell Replacement in the Mammalian Retina (Author)
  • Maike Assmann - , German Center for Infection Research, Partner Site Hamburg-Lübeck-Borstel-Riems (Author)
  • Alexander Dalpke - , Institute of Medical Microbiology and Virology (Author)
  • Ulrich E. Schaible - , German Center for Infection Research, Partner Site Hamburg-Lübeck-Borstel-Riems (Author)
  • Diana Dudziak - , Friedrich-Alexander University Erlangen-Nürnberg, Deutsches Zentrum Immuntherapie (DZI) and Medical Immunology Campus Erlangen, University Hospital at the Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Bernd Schröder - , Institute of Physiological Chemistry (Author)

Abstract

Signal peptide peptidase–like 2a (SPPL2a) is an aspartyl intramembrane protease essential for degradation of the invariant chain CD74. In humans, absence of SPPL2a leads to Mendelian susceptibility to mycobacterial disease, which is attributed to a loss of the dendritic cell (DC) subset conventional DC2. In this study, we confirm depletion of conventional DC2 in lymphatic tissues of SPPL2a2/2 mice and demonstrate dependence on CD74 using SPPL2a2/2 CD742/2 mice. Upon contact with mycobacteria, SPPL2a2/2 bone marrow–derived DCs show enhanced secretion of IL-1b, whereas production of IL-10 and IFN-b is reduced. These effects correlated with modulated responses upon selective stimulation of the pattern recognition receptors TLR4 and Dectin-1. In SPPL2a2/2 bone marrow–derived DCs, Dectin-1 is redistributed to endosomal compartments. Thus, SPPL2a deficiency alters pattern recognition receptor pathways in a CD74-dependent way, shifting the balance from anti- to proinflammatory cytokines in antimycobacterial responses. We propose that in addition to the DC reduction, this altered DC functionality contributes to Mendelian susceptibility to mycobacterial disease upon SPPL2a deficiency.

Details

Original languageEnglish
Pages (from-to)164-180
Number of pages17
JournalJournal of Immunology
Volume206
Issue number1
Publication statusPublished - 1 Jan 2021
Peer-reviewedYes

External IDs

PubMed 33239420

Keywords

ASJC Scopus subject areas