Deficiency of the Intramembrane Protease SPPL2a Alters Antimycobacterial Cytokine Responses of Dendritic Cells

Gradtke AC, Mentrup T, Lehmann C, Cabrera-Cabrera F, Desel C, Okakpu D, Assmann M, Dalpke A, Schaible UE, Dudziak D, Schroder B (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Journal of Immunology American Association of Immunologists

Book Volume: 206

Pages Range: 164-+

Journal Issue: 1

DOI: 10.4049/jimmunol.2000151

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(-/-) CD74(-1-) mice. Upon contact with mycobacteria, SPPL2a(-/-) bone marrow-derived DCs show enhanced secretion of IL-1 beta, whereas production of IL-10 and IFN-beta 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.

Authors with CRIS profile

Christian Lehmann Department of Dermatology Diana Dudziak Professur für die Biologie Dendritischer Zellen

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

A080: Control of immune responses by inflammasomes in primary dendritic cells Jan. 1, 2020 - Dec. 31, 2022

Involved external institutions

Technische Universität Dresden DE Germany (DE) Christian-Albrechts-Universität zu Kiel DE Germany (DE) Forschungszentrum Borstel - Leibniz-Zentrum für Medizin und Biowissenschaften / Research Center Borstel - Leibniz-Center for Medicine and Biosciences DE Germany (DE)

How to cite

APA:

Gradtke, A.-C., Mentrup, T., Lehmann, C., Cabrera-Cabrera, F., Desel, C., Okakpu, D.,... Schroder, B. (2021). Deficiency of the Intramembrane Protease SPPL2a Alters Antimycobacterial Cytokine Responses of Dendritic Cells. Journal of Immunology, 206(1), 164-+. https://doi.org/10.4049/jimmunol.2000151

MLA:

Gradtke, Ann-Christine, et al. "Deficiency of the Intramembrane Protease SPPL2a Alters Antimycobacterial Cytokine Responses of Dendritic Cells." Journal of Immunology 206.1 (2021): 164-+.

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