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.
Highlights
Allergic asthma is an inflammatory disease of the airways that develops in response to harmless aeroallergens such as the ones from house dust mite (HDM)
To understand the mechanisms underlying the reduced potency of the C5a receptor 1 (C5aR1) conventional dendritic cells (cDCs) to efficiently induce T cell proliferation, we evaluated the expression of MHC-II and the costimulatory molecules CD40, CD80, CD86 and OX40L in C5aR1+ and C5aR1− cDCs under steady-state conditions and 24 h after HDM/OVA exposure (Figure 3)
C5aR1 blockade, the frequency of activated CD4+ T cells increased to 60 ± 10% in contrast to the treatment with the isotype control, which resulted in activation of 30 ± 10% of the CD4+ T cells. These findings demonstrate that signaling through C5aR1 is an important mechanism to control CD4+ T cell proliferation by pulmonary CD11b+ cDCs (Figure 6A)
Summary
Allergic asthma is an inflammatory disease of the airways that develops in response to harmless aeroallergens such as the ones from house dust mite (HDM). Dendritic cells (DCs) have been shown to play a key role for the development of maladaptive Th2/Th17 responses in allergic asthma [1]. DCs were initially described as a homogeneous population of CD11c+ MHC-II+ cells [2]. Ontogenetic studies provided detailed insights into the development of distinct DC lineages. Based on such studies, at least four DC subtypes with distinct functions can be differentiated [3]. At least four DC subtypes with distinct functions can be differentiated [3]
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