SLAMF7 and SLAMF8 receptors shape human plasmacytoid dendritic cell responses to intracellular bacteria
Joaquín Miguel Pellegrini, Anne Keriel, Laurent Gorvel, Sean Hanniffy, Vilma Arce-Gorvel, Mile Bosilkovski, Javier Solera, Stéphane Méresse, Sylvie Mémet, Jean-Pierre Gorvel
Joaquín Miguel Pellegrini, Anne Keriel, Laurent Gorvel, Sean Hanniffy, Vilma Arce-Gorvel, Mile Bosilkovski, Javier Solera, Stéphane Méresse, Sylvie Mémet, Jean-Pierre Gorvel
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Research Article Immunology Infectious disease Microbiology

SLAMF7 and SLAMF8 receptors shape human plasmacytoid dendritic cell responses to intracellular bacteria

Abstract

Plasmacytoid dendritic cells (pDCs), professional type I IFN–producing cells, have been implicated in host responses against bacterial infections. However, their role in host defense is debated, and the operating molecular mechanisms are unknown. Certain signaling lymphocyte activation molecule family (SLAMF) members act as microbial sensors and modulate immune functions in response to infection. Here, human blood transcriptomic analyses reveal the involvement of SLAMF7 and SLAMF8 in many infectious diseases, with elevated levels associated with type I IFN responses in salmonellosis and brucellosis patients. We further identify SLAMF7 and SLAMF8 as key regulators of human pDC function. They activate pDC maturation and cytokine production during infection with bacteria that induce acute (Salmonella) or chronic (Brucella) inflammation. SLAMF7 and SLAMF8 signal through NF-κB, IRF7, and STAT-1, and limit mitochondrial ROS accumulation upon Salmonella infection. Remarkably, this SLAMF7/8-dependent control of mitochondrial ROS levels favors bacterial persistence and NF-κB activation. Overall, our results unravel essential shared multifaceted roles of SLAMF7 and SLAMF8 in finely tuning human pDC responses to intracellular bacterial infections with potential for future diagnostic and therapeutic applications.

Authors

Joaquín Miguel Pellegrini, Anne Keriel, Laurent Gorvel, Sean Hanniffy, Vilma Arce-Gorvel, Mile Bosilkovski, Javier Solera, Stéphane Méresse, Sylvie Mémet, Jean-Pierre Gorvel

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Figure 3

SLAMF7 and SLAMF8 are expressed at high levels in pDCs.

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SLAMF7 and SLAMF8 are expressed at high levels in pDCs. (A and B) SLAMF7...
(A and B) SLAMF7 and SLAMF8 surface expression on the different cell types of PBMCs from HDs was analyzed by spectral flow cytometry. (A) Representative histograms at the resting state with positivity indicated by a vertical gray bar are shown. n = 12. (B) Analysis 24 hours after treatment (or not) of PBMCs with R848 or E. coli LPS (100 ng/mL) for 24 hours. One donor per n; n = 12. Dot plots represent the median fluorescence intensity (MFI; color) and the percentage of expression (size) in a determined cell type. Color and size codes are indicated on the right. (C) Purified human primary pDCs were stimulated with CpG (TLR9 ligand, 100 ng/mL), poly(I:C) (TLR3 ligand, 100 ng/mL), PAM3CSK4 (TLR1/2 ligand, 100 ng/mL), flagellin (TLR5 ligand, 100 ng/mL), E. coli LPS (TLR4 ligand, 100 ng/mL), R848 (TLR7/8 ligand, 100 ng/mL), or B. melitensis LPS (10 μg/mL) for 24 hours. Then, SLAMF7 and SLAMF8 levels of expression were evaluated by flow cytometry. Histograms presenting MFI of SLAMF7 and SLAMF8 are shown. Mean ± SD. One donor per n; n = 11. Significant differences are indicated. For each individual experiment, values for CpG or R848 conditions were always above those of the mock-treated cells for SLAMF7, and above (n = 10) or similar (n = 1) for SLAMF8 MFI. One-way ANOVA followed by Dunnett’s multiple-comparison test. ****P < 0.0001. (D) Representative confocal microscopy images of CAL-1 cells in basal conditions stained for SLAMF7 (turquoise, top left and right panels), SLAMF8 (red, bottom left and right panels), LAMP-1 (magenta, middle and right panels), and nuclei (DAPI, blue, right panels). Scale bars: 10 μm. n = 5.