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

Abstract

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− but not C5aR1+ cDCs strongly induced T cell proliferation of OVA-reactive transgenic CD4+ T cells after re-exposure to antigen in vitro. C5aR1− 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 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.

C5aR1 Activation Drives Early IFN-γ Production to Control Experimental Toxoplasma gondii Infection

“…Previously, we demonstrated that C5aR1 controls the production of cytokines and chemokines that are associated with resistance to T. gondii infection ( 43 – 46 ). Here, we focused on the impact of C5aR1 activation on IL-12 as the main driver of IFN-γ production from NK cells and the development of protective Th1 immunity ( 4 , 10 , 47 ).…”

Current research and unmet needs in allergy and immunology in Germany: report presented by the DGfI and DGAKI task force Allergy & Immunology

“…Activated canonically by pathogen‐associated molecular patterns associated with allergens or non‐canonically by allergen‐ or cell‐derived proteases, C3 or C5 are cleaved into different potent inflammatory mediators. Of those, the anaphylatoxins C3a and C5a exert not only strong pro‐allergic effector functions through activation of innate effector cells such as neutrophils, eosinophils and MC but also control allergen sensitization at the interface between dendritic, B and T cells, at least in mice [2].…”

Tackling COVID‐19 infection through complement‐targeted immunotherapy

“…Similar to C3a and in concert with C3a, C5a can drive a proinflammatory environment through its strong chemotactic properties on neutrophils, monocytes, eosinophils, basophils, mast cell, and dendritic cell (DC) and its potency to activate such cells to release ROS, lysosomal enzymes, and proinflammatory cytokines such as IL‐1β, TNF‐α, IL‐6, and chemokines of the CC and CXC families (Figure 2). C5a also drives the activation and differentiation of T cells through DC maturation downstream of C5aR1 (Antoniou et al, 2020; Weaver et al, 2010). Also, C5a controls histamine‐induced increase in vasopermeability (Kordowski et al, 2019) and drives the production of metabolites of the arachidonic acid lipoxygenase and COX pathways resulting in increased production of LTB 4 or PGE 2 , both of which increase microvascular permeability (Karasu, Nilsson, Köhl, Lambris, & Huber‐Lang, 2019; Klos et al, 2009).…”