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.