Signaling C-type lectin receptors in antimycobacterial immunity

The mammalian innate immune system is composed of phagocytes such as macrophages and dendritic cells that serve as the first line of defense against microbial infections. These cells express various pattern recognition receptors (PRRs) that recognize specific pathogen-associated molecular patterns (PAMPs) on the surface of or inside microorganisms [1]. PRRs such as Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and Nucleotide-binding Oligomerization Domain (NOD)-like receptors (NLRs) have been widely studied in antimicrobial immunity and homeostasis. These PRRs have also been implicated in antimycobacterial immunity, with CLRs recently receiving considerable attention. CLRs are a large family of proteins containing at least 1 carbohydrate-recognition domain (CRD) that in most cases binds a range of carbohydrate-based PAMPs, including trehalose 6,6’ dimycolate (TDM), lipoarabinomannan (LAM), lipomannan (LM), and phosphatidylinositol mannosides (PIMs) [2–4]. Interactions of CLRs with mycobacterial PAMPs induce intracellular signaling that triggers responses ranging from cytokine production to induction of adaptive immunity (Table 1). Here, we discuss signaling CLRs that recognize mycobacterial PAMPs and contribute to antimycobacterial immunity. We focus on the receptors that signal through the Spleen tyrosine kinase (Syk)/Caspase recruitment domain family member 9 (CARD9) pathway, including Dectin-1, Dectin-2, macrophage-inducible C-type lectin (Mincle), C-type lectin superfamily member 8 (Clecsf8) also called macrophage C-type lectin (MCL), and dendritic cell immunoactivating receptor (DCAR) (Fig 1). Table 1 C-type lectin receptors, mycobacterial ligands, and their effects on pro-inflammatory cytokine production and contributions in host resistance to mycobacterial infections in vivo. C-type lectin receptor Mtb ligand Cellular expression Effects on pro-inflammatory cytokine production Role in host resistance to mycobacterial infection References Dectin-1 unknown DCs, monocytes, macrophages, neutrophils, eosinophils, mast cells, and lung epithelium ↑IL-6, IL-23, IL-1β, TNF-α, IL-12p40, and IL-17 Dispensable for host resistance to Mycobacterium tuberculosis H37Rv infection in mice [5, 7, 9–11, 35] Dectin-2 ManLAM DCs, monocytes, tissue macrophages, CD8+ T cells, and CD19+ B cells ↑TNF-α, IL-6, and IL-17 Survival studies not performed. Required to control lung damage during M. avium infection. [4, 12, 14, 36] Mincle TDM Monocytes, macrophages, neutrophils, myeloid DCs, and B cells. ↑IL-8, IL-6 andIL-1β Required for bacterial clearance. Inconsistent results on essentiality. [4, 17, 19, 21–23] ClecSF8 (MCL) TDM Neutrophils, monocytes, and DCs ↑IL-6, TNF-α and IL-1β Required for resistance to M. bovis BCG and M. tuberculosis H37Rv infection in mice [25, 28, 29] Mannose receptor ManLAM, DIM, mannosylated proteins Macrophages and MDCs ↑IFN-γ Survival studies not performed [10, 34, 37, 38] DC-SIGN ManLAM, PIMs, mannosylated glycoproteins Myeloid DCs and macrophages ↑IFN-γ hSIGN transgenic mice resistant to high-dose M. tuberculosis H37Rv infection. SIGNR3 KO mice have elevated CFUs. [10, 32, 33, 39] DCAR PIMs Peritoneal macrophages, monocyte-derived inflammatory cells in lung and spleen ↑IFN-γ and IL-12 Survival studies not performed. High CFU in DCAR KO mice infected with BCG or H37Rv. [4, 31] Open in a separate window Abbreviations: CFU, colony-forming unit; ClecSF8, C-type lectin superfamily member 8; DC, dendritic cells; DC-SIGN, Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin; DCAR, dendritic cell immunoactivating receptor; DIM, Phthiol Dimycocerosates; KO, knock-out; ManLAM, Mannose-caped Lipoarabinomannan; Mincle, macrophage-inducible C-type lectin; MCL, macrophage C-type lectin; Mtb, Mycobacterium tuberculosis; PIM, Phosphatidyinositol Mannosides; TDM, Trehalose Dimycolate.