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

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