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Published on: November 4, 2016
Deficiency of the Intramembrane Protease SPPL2a Alters Antimycobacterial Cytokine Responses of Dendritic Cells
Ann-Christine Gradtke1, Torben Mentrup1, Christian H K Lehmann2,3,4,5
1Institute of Physiological Chemistry, Technische Universität Dresden, D-01307 Dresden, Germany.
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 SPPL2a mice and demonstrate dependence on CD74 using SPPL2a mice. Upon contact with mycobacteria, SPPL2a bone marrow-derived DCs show enhanced secretion of IL-1β, whereas production of IL-10 and IFN-β is reduced. These effects correlated with modulated responses upon selective stimulation of the pattern recognition receptors TLR4 and Dectin-1. In SPPL2a 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.
Insights
Signal peptide peptidase-like 2a (SPPL2a) deficiency impairs dendritic cell function, increasing susceptibility to mycobacterial disease. This involves altered cytokine production and pattern recognition receptor signaling, highlighting SPPL2a
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Signal peptide peptidase-like 2a (SPPL2a) is crucial for degrading the invariant chain CD74.
- Human SPPL2a deficiency causes Mendelian susceptibility to mycobacterial disease due to loss of conventional dendritic cell subset 2 (cDC2).
- The precise mechanisms linking SPPL2a deficiency to altered immune responses remain unclear.
Purpose of the Study:
- To investigate the role of SPPL2a in dendritic cell (DC) function and antimycobacterial responses in mice.
- To elucidate the CD74-dependent mechanisms underlying SPPL2a's impact on DC subsets and cytokine profiles.
- To explore how SPPL2a deficiency affects pattern recognition receptor (PRR) signaling pathways.
Main Methods:
- Confirmation of cDC2 depletion in lymphatic tissues of SPPL2a-deficient mice.
- Analysis of cytokine secretion (IL-1β, IL-10, IFN-β) by SPPL2a-deficient bone marrow-derived DCs upon mycobacterial exposure.
- Assessment of TLR4 and Dectin-1 signaling pathways, including Dectin-1 subcellular localization.
Main Results:
- SPPL2a deficiency leads to depletion of cDC2 and altered cytokine production in DCs, with increased IL-1β and reduced IL-10/IFN-β.
- These changes are CD74-dependent and correlate with modulated responses to TLR4 and Dectin-1 stimulation.
- Dectin-1 redistribution to endosomal compartments was observed in SPPL2a-deficient DCs.
Conclusions:
- SPPL2a deficiency alters PRR pathways in a CD74-dependent manner, skewing cytokine balance towards pro-inflammatory responses against mycobacteria.
- Both cDC2 reduction and altered DC functionality contribute to increased susceptibility to mycobacterial disease in SPPL2a deficiency.
- SPPL2a plays a critical role in maintaining DC homeostasis and effective antimycobacterial immunity.
