Innate Immune Activation Is a Strong Suppressor of CCL22 and Impedes Regulatory T Cell–Dendritic Cell Interaction

Piseddu, Ignazio ; Gärtig, Jan; Eiber, Stephan; Moder, Stefan; Thaler, Raffael; Thaler, Matthias; Gruen, Juliane; Vornhülz, Marlies ; Bahner, Kevin; Messa, Luana; Kühnemuth, Benjamin; Müller, Jennifer; Schnell, Konstantin; Beimert, Antonia; Perleberg, Carolin; Röhrle, Natascha; Knott, Maximilian Martin Ludwig; Hammann, Linda; Wittmann, Vanessa; Layritz, Patrick; Rapp, Moritz; Bourquin, Carole; Mayerle, Julia ; Endres, Stefan und Anz, David (26. März 2025): Innate Immune Activation Is a Strong Suppressor of CCL22 and Impedes Regulatory T Cell–Dendritic Cell Interaction. In: Immunology [Forthcoming]

Abstract

The chemokine CCL22 is constitutively expressed at high levels in lymphoid organs, where it controls immunity by promoting contacts between dendritic cells (DC) and regulatory T cells (Treg). However, its regulation and impact in the context of pattern recognition receptor (PRR) stimulation and microbial infection are unknown. Here we show that CCL22 levels in lymphoid organs of mice were strongly suppressed upon stimulation with TLR agonists. In vitro, activation of Toll-like receptors (TLR), RIG-I like helicases (RLH) and stimulator of interferon genes (STING) resulted in a potent downregulation of CCL22. Mechanistically, the suppression of DC-derived CCL22 secretion was exerted by inflammatory cytokines such as IFN-α, IFN-γ and IL-10 released upon TLR activation by B and T cells. Decreased CCL22 synthesis correlated with reduced frequencies of cellular clustering between Treg and DC in co-cultures. CCL22 suppression was also observed upon microbial infection, since CCL22 levels were significantly reduced in lymphoid organs of mice upon injection of Salmonella typhimurium. As a clinical correlate, CCL22 serum concentrations were decreased in patients with sepsis compared to controls. Taken together, we demonstrate a strong and long-lasting suppression of CCL22 as a consequence of innate immune activation. In the context of microbial infection, transient reduction of CCL22 reduces Treg-DC interactions and may thereby represent a mechanism to weaken Treg function in order to enable an effective immune response and pathogen clearance.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Klinikum der LMU München > Medizinische Klinik und Poliklinik II (Gastroenterologie, Hepatologie)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0019-2805
• Bemerkung: Online first published 26.03.2025
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 490846870