Figure 2.

PRR and signaling pathways that lead to differentiation of antifungal T-helper cells. Recognition of fungal pathogen–associated molecular patterns (PAMPs) is mediated by TLRs and CLRs. The binding of fungi or β-glucan to Dectin-1 recruits SYK to the two phosphorylated receptors, which leads to the formation of a complex involving Card9, BCL10, and MALT1 (BCM). This results in the release of NF-κB consisting of either p65–p50 or REL–p50 dimers into the nucleus (Geijtenbeek and Gringhuis 2009). Syk activation also induces the noncanonical NF-κB pathway mediated by NF-κB-inducing kinase (NIK) and the nuclear translocation of p52–RELB dimers. Dectin-1 enhances TLR2 and TLR4-induced cytokines in a Syk-independent manner through the serine/threonine protein kinase RAF1 by Ras proteins, which leads to the phosphorylation of p65 (Gringhuis et al. 2009). Among other cytokines, these pathways lead to the production of IL-6, IL-23, and IL-12 that induce Th17 and Th1 cells, respectively. Dectin-1 recognition of C. albicans can also activate the NLRP3 inflammasome through a mechanism that involves Syk, ROS, and potassium efflux (Poeck and Ruland 2010). Fungus-induced pro-IL-1β is cleaved by active caspase-1 to bioactive IL-1β to favor Th17 development. Dectin-2 activation leads to FcR-γ-dependent recruitment and phosphorylation of Syk and activated NF-κB and MAPKs (p38, JNK, and Erk) (Saijo et al. 2010). Card9 is required for the activation of NF-κB and production of cytokines that lead to Th17 cell differentiation. Recognition of α-mannose in Malassezia species by Mincle activates the FcR-γ-Syk-Card9 pathway and translocates NF-κB into the nucleus to induce the activation of proinflammatory cytokines (Yamasaki et al. 2009). *Although fungal PAMPs have yet to show the ability to induce a distinct T-helper subset by this pathway, the mycobacterial cord factor and its synthetic analog are potent adjuvants for the differentiation of Mincle-induced Th1 and Th17 cells (Schoenen et al. 2010). Dectin-3 (MCL, Clec4d, or Clecsf8) also recognizes α-mannan from C. albicans (Zhu et al. 2013) and TDM from M. tuberculosis (Miyake et al. 2013). Dectin-3 can dimerize with Dectin-2 (Zhu et al. 2013) and Mincle (Lobato-Pascual et al. 2013). It is unclear whether the induction of Th17 and Th1 cells requires recognition of fungal PAMPs by homo- versus heterodimers of Dectin-2. The MR lacks a classical signaling motif in its short cytoplasmic tail, but it induces proinflammatory cytokines that have been implicated in Th17 and Th1 differentiation (Willment and Brown 2008). Although MR-dependent triggering of human memory T cells produced IL-17, further studies with naïve T cells will be needed to establish the role of the MR in Th17 cell differentiation (van de Veerdonk et al. 2009). Myd88 is critical for the signaling of TLR2 and TLR4. Phospholipomannans and O-linked mannans are recognized by TLRs at the plasma membrane, whereas fungal nucleic acids are sensed by endosomal TLRs and induce NF-κB-, MAPK-, and IRF-dependent cytokine production. TLR2 signaling is thought to generate weaker proinflammatory signals, but induce strong stimulation of TGF-β and IL-10 that induces Treg cells (Netea et al. 2004a; Sutmuller et al. 2006).