IL-10 and TGF-β Control of Dendritic Cells at Environmental Interfaces

Abstract

Dendritic cells (DC) are necessary to maintain homeostasis and are essential in regulating immune responses. DC induce effector T cell responses to invading pathogens and promote regulatory T cell (Treg) differentiation to harmless antigens. Interleukin-10 (IL-10) and transforming growth factor β (TGF-β) are anti-inflammatory cytokines displaying potent tolerogenic abilities. Both cytokines are secreted by and act on a plethora of (non-) immune cells including T cells and DC. In vitro studies demonstrated that both IL-10 and TGF-β attenuate DC maturation and function. In this thesis, we investigated the role of IL-10 and TGF-β signaling in DC in vivo, using mice with a DC-specific deletion of the IL-10Rα and TGF-βR1, respectively (DC-IL10R-/- and DC-TβR1-/- mice). Chapter 1 provides a general introduction. In Chapter 2 we first analyzed DC-IL10R-/- mice in the steady state. In contrast to in vitro studies, IL10R-deficient DC did not express enhanced surface MHC-II or co-stimulatory molecules in vivo. However, upon stimulation, IL10R-deficient DC secreted elevated amounts of pro-inflammatory cytokines. We establish that IL-10 control of DC is dispensable during T cell priming in skin-draining LN, but crucial in regulating the reactivation of effector/memory T cells in the skin. Chapter 3 continues to focus on the IL-10 regulation of skin DC, using a cutaneous infection model of Leishmania major (L. major) parasites. Our results suggest that IL-10 control of DC is important during the acute phase but not the latent phase of leishmaniasis. In Chapter 4, we describe DC-IL10R-/- mice which spontaneously develop enteropathy, similar to patients with celiac disease. We conclude that IL-10 control of DC is necessary to dampen effector/memory Th1/Th17 cell reactivation and maintain immune homeostasis in the small intestine. In Chapter 5, we show that DC-IL10R-/- mice develop less asthma compared to controls and hypothesize that IL-10R-deficient DC secrete elevated levels of IL-10 which could enhance Treg activity and regulate asthma in situ. In Chapter 6 we demonstrate that TGF-β is necessary for the maintenance of LC in the epidermis but that TGF-β-signaling is dispensable for the homeostasis of other skin DC subsets, notably Langerin+ dermal DC. Our results also demonstrate that TGF-β control of dermal DC is dispensable during CHS. In Chapter 7 we establish that TGF-β control of colonic DC is essential to for their tolerogenic conditioning, and therefore is crucial to prevent colitis. Chapter 8 is a general discussion and future perspectives.