Allergen-Induced C5a/C5aR1 Axis Activation in Pulmonary CD11b⁺ cDCs Promotes Pulmonary Tolerance through Downregulation of CD40

• Main Authors: Konstantina Antoniou, Fanny Ender, Tillman Vollbrandt, Yves Laumonnier, Franziska Rathmann, Chandrashekhar Pasare, Harinder Singh, Jörg Köhl
• Format: Article
• Language: English
• Published: MDPI AG 2020-01-01
• Series: Cells
• Subjects: allergic asthma; complement; conventional dendritic cell; c5a receptor; cd40; house-dust-mite
• Online Access: https://www.mdpi.com/2073-4409/9/2/300
• ISSN: 2073-4409

Activation of the C5/C5a/C5a receptor 1 (C5aR1) axis during allergen sensitization protects from maladaptive T cell activation. To explore the underlying regulatory mechanisms, we analyzed the impact of C5aR1 activation on pulmonary CD11b⁺ conventional dendritic cells (cDCs) in the context of house-dust-mite (HDM) exposure. BALB/c mice were intratracheally immunized with an HDM/ovalbumin (OVA) mixture. After 24 h, we detected two CD11b⁺ cDC populations that could be distinguished on the basis of C5aR1 expression. C5aR1^&#8722; but not C5aR1⁺ cDCs strongly induced T cell proliferation of OVA-reactive transgenic CD4⁺ T cells after re-exposure to antigen in vitro. C5aR1^&#8722; cDCs expressed higher levels of MHC-II and CD40 than their C5aR1⁺ counterparts, which correlated directly with a higher frequency of interactions with cognate CD4⁺ T cells. Priming of OVA-specific T cells by C5aR1⁺ cDCs could be markedly<i> </i>increased by in vitro blockade of C5aR1 and this was associated with increased CD40 expression. Simultaneous blockade of C5aR1 and CD40L on C5aR1⁺ cDCs decreased T cell proliferation. Finally, pulsing with OVA-induced C5 production and its cleavage into C5a by both populations of CD11b⁺ cDCs. Thus, we propose a model in which allergen-induced autocrine C5a generation and subsequent C5aR1 activation in pulmonary CD11b⁺ cDCs promotes tolerance towards aeroallergens through downregulation of CD40.