SLAMF7 and SLAMF8 receptors shape human plasmacytoid dendritic cell responses to intracellular bacteria
Joaquín Miguel Pellegrini, … , Sylvie Mémet, Jean-Pierre Gorvel
Joaquín Miguel Pellegrini, … , Sylvie Mémet, Jean-Pierre Gorvel
Published April 15, 2025
Citation Information: J Clin Invest. 2025;135(8):e182467. https://doi.org/10.1172/JCI182467.
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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 6

SLAMF7 or SLAMF8 engagement in human primary pDCs elicits strong cell activation, as well as high cytokine and type I and III IFN secretion.

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SLAMF7 or SLAMF8 engagement in human primary pDCs elicits strong cell ac...
(A–C) Purified human primary pDCs from healthy individuals were infected with Salmonella Typhimurium (MOI of 25) and, after 1 hour, washes, and addition of gentamicin, SLAMF7 or SLAMF8 were engaged by cross-linking with 10 μg/mL of a specific antibody (anti-SLAMF7, blue filled circles, or anti-SLAMF8, pink filled circles) or its isotype control (empty circles) for 1 hour. Cells were then analyzed at 24 hours p.i. (A) Expression (MFI) of human pDC activation markers (HLA-DR, left; CD80, middle left; CD86, middle right; and PD-L1, right) was determined by flow cytometry. Each individual point represents 1 independent experiment. Mean ± SD. One donor per n; n = 6. Significant differences are indicated. Paired 2-tailed t test. *P < 0.05; **P < 0.01. (B) Heatmap of selected cytokines and chemokines, analyzed by multiplex flow cytometry in cell culture supernatants. Z scores of cytokine/chemokine concentrations are shown with intensity of the color representing the degree of variation in each condition from HD pDCs treated with the isotype control antibodies. One donor per n; n = 6. (C) Secretion of different IFN type I and III subspecies and of CXCL10 (pg/mL) determined in cell culture supernatants using multiplex flow cytometry. Each individual point represents 1 independent experiment. Mean ± SD. One donor per n; n = 6. Significant differences are shown. Paired 2-tailed t test. *P < 0.05; **P < 0.01. No P value indicates not significant.