Dectin-1-Syk-CARD9 Signaling Pathway in TB Immunity

Abstract

One of the first steps toward mounting an effective immune response to Mycobacterium tuberculosis (Mtb) is recognition of the pathogen through pattern-recognition receptors (PRRs) expressed by innate immune cells. Activation of the PRR Dectin-1 by an unknown mycobacterial ligand triggers an intracellular signaling cascade involving numerous proteins, including spleen tyrosine kinase, protein kinase C-delta, and caspase recruitment domain family member 9, some of which have been shown to influence host immune response to TB infection. Here, we review the role of Dectin-1 signaling pathway in anti-mycobacterial immunity and discuss its contribution in the control of Mtb infection, and potential applications in TB vaccine adjuvanticity.

Keywords: C-type lectin receptors; Mycobacterium tuberculosis; TB immunity; dectin-1; innate immunity; pathogen-associated molecular patterns; pattern-recognition receptors; tuberculosis.

Figure 1

Dectin-1 structure. Dectin-1 consists of an extracellular C-type lectin domain, which is the carbohydrate-recognition domain (CRD) that binds ligands such as β-glucans. The CRD is attached by a stalk to a transmembrane region. Dectin-1 undergoes N-linked glycosylation on the CRD (mice) or stalk region (humans), shown in red and blue, respectively. The intracytoplasmic region comprises an immunoreceptor tyrosine-based activation motif- (ITAM)-like motif, or hemITAM, which initiates intracellular signaling.

Figure 2

Recognition of Mycobacterium tuberculosis (Mtb) by Dectin-1. An unknown Mtb ligand is recognized by Dectin-1, which is then tyrosine phosphorylated at its hemITAM residue by Src kinases (data not shown). This creates a docking site for spleen tyrosine kinase (Syk). Syk associates with a caspase recruitment domain family member 9 (CARD9)/B-cell lymphoma 10 (BCL-10)/mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) protein complex, resulting in activation of the transcription factor nuclear factor κB (NF-κB). Pro-inflammatory cytokine production follows, which induce an adaptive T cell response. Dectin-1-dependent signaling can also occur in neutrophils, where they induce reactive oxygen species (ROS) production.