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

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.