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 7

SLAMF7 and SLAMF8 limit Salmonella elimination by human pDCs.

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SLAMF7 and SLAMF8 limit Salmonella elimination by human pDCs. (A–C) CAL-...
(A–C) CAL-1 and SLAMF7- or SLAMF8-silenced (2 clones, A and B, per SLAMF-KD type) and shCTRL CAL-1 cells were infected with DsRed–S. Typhimurium (MOI 25) for the indicated times p.i. One-way ANOVA followed by Dunnett’s multiple-comparison test. (A) Percentages of DsRed-Salmonella+ cells determined by flow cytometry at 2 hours (Internalization), 24 hours, and 48 hours p.i. Each individual point represents 1 independent experiment. Mean ± SD. n = 4–5. (B) Bacterial intracellular burden (CFU/mL, log) at indicated time points. Each individual point represents 1 independent experiment. Mean ± SD. n = 2 (2 hours), n = 5 (24 hours). (C) Kinetics experiment. Salmonella loads (CFU/mL, log) at indicated time points. Each individual point represents 1 independent experiment. Mean ± SD. n = 4. (D) Left: Confocal images of CAL-1 and SLAMF-silenced cells infected with DsRed–S. Typhimurium at 24 hours p.i. Salmonella, yellow; actin, purple. Scale bars: 20 μm. n = 3. Right: Violin plots depicting the number of bacteria per cell. Pooled data (total cells counted, 50–66). Multiple-comparison Kruskal-Wallis test followed by post hoc Dunn’s test. (E) Primary human cells were infected with DsRed–S. Typhimurium (MOI 25) and, after 1 hour, washes, and addition of gentamicin, SLAMF7 or SLAMF8 were engaged by cross-linking with a specific antibody or its isotype control. Percentages of DsRed-Salmonella+ cells at 24 hours p.i. Each individual point represents 1 independent experiment. Mean ± SD. One donor per n; SLAMF7, n = 7; SLAMF8, n = 6. Paired 2-tailed t test. (F) Salmonella loads (CFU/mL, log) at 24 hours p.i. in human primary pDCs treated as in E. Each individual point represents 1 independent experiment. Mean ± SD. One donor per n; n = 7. Paired 2-tailed t test. For all panels, significant differences are shown. *P < 0.05; **P < 0.01; ***P < 0.001. No P value indicates not significant.