Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17

Abstract

The C-type lectin dectin-1 binds to yeast and signals through the kinase Syk and the adaptor CARD9 to induce production of interleukin 10 (IL-10) and IL-2 in dendritic cells (DCs). However, whether this pathway promotes full DC activation remains unclear. Here we show that dectin-1-Syk-CARD9 signaling induced DC maturation and the secretion of proinflammatory cytokines, including IL-6, tumor necrosis factor and IL-23, but little IL-12. Dectin-1-activated DCs 'instructed' the differentiation of CD4+ IL-17-producing effector T cells (T(H)-17 cells) in vitro, and a dectin-1 agonist acted as an adjuvant promoting the differentiation of T(H)-17 and T helper type 1 cells in vivo. Infection with Candida albicans induced CARD9-dependent T(H)-17 responses to the organism. Our data indicate that signaling through Syk and CARD9 can couple innate to adaptive immunity independently of Toll-like receptor signals and that CARD9 is required for the development of T(H)-17 responses to some pathogens.

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of TH1/TH17 polarization

“…However, a partial defect in antigen processing cannot be formally excluded. Interestingly, PLCg2 À/À BMDC were less activated than WT BMDC also under steady state conditions, perhaps due to reduced function of other ITAMdependent receptors that are constitutively engaged during homeostasis.It has been shown that Syk and CARD9 promote secretion of cytokines such as IL-6 and IL-23 in response to b-glucan, generating the cytokine microenvironment that favors the expansion of T H 17 effector T cells [18,36]. In our study, PLCg2-deficient BMDC recapitulated both the Syk-deficient and CARD9-deficient phenotypes for Dectin-1-mediated responses.…”

“…Thus, one would predict that lack of Syk and/or BTK in DC affects Dectin-1-mediated inflammatory cytokine production, as PLCg2-deficiency does. Accordingly, a previous study showed that lack of Syk impairs Dectin-1 function [8,9,18]. To further extend this study, we asked whether BTK is required for cytokine responses to b-glucan.…”

“…Dectin-1 triggers cytokine production through downstream signaling mediators such as MAPK [3,18]. To determine how PLCg2-deficiency impairs Dectin-1-induced cytokine production, we analyzed MAPK activation.…”

TLR2‐activated human langerhans cells promote Th17 polarization via IL‐1β, TGF‐β and IL‐23

“…The requirement of the presence of DC is further supported by studies with murine bone marrowderived DC. DC stimulated by curdlan, a dectin-1 agonist, were found to effectively promote Th17 differentiation from CD4 1 T cells via an autonomous pattern recognition pathway [38]. However, to our knowledge the induction of Th17 by TLR-activated skin-DC, in our study substituted for methodical reasons by CD1c 1 MoLC, has not been reported before.…”

The essential function of CARD9 in diet‐induced inflammation and metabolic disorders in mice

“…CARD9 is closely associated with immune responses, immune cell activation 3, 4 and inflammatory response 5. CARD9 utilizes B‐Cell lymphoma 10 (BCL10) and MALT1 to mediate Dectin‐1 signalling for the activation of nuclear factor‐k‐gene binding (NF‐κB), p38 mitogen‐activated protein kinase (p38 MAPK), and c‐Jun N‐terminal kinase (JNK) 2, 3.…”