How location governs toll-like receptor signaling

Abstract

Toll-like receptors (TLRs) are a family of innate immune system receptors responsible for recognizing conserved pathogen-associated molecular patterns (PAMPs). PAMP binding to TLRs initiates intracellular signaling pathways that lead to the upregulation of a variety of costimulatory molecules and the synthesis and secretion of various cytokines and interferons by cells of the innate immune system. TLR-induced innate immune responses are a prerequisite for the generation of most adaptive immune responses, and in the case of B cells, TLRs directly regulate signaling from the antigen-specific B-cell receptor. The outcome of TLR signaling is determined, in part, by the cells in which they are expressed and by the selective use of signaling adaptors. Recent studies suggest that, in addition, both the ligand recognition by TLRs and the functional outcome of ligand binding are governed by the subcellular location of the TLRs and their signaling adaptors. In this review we describe what is known about the intracellular trafficking and compartmentalization of TLRs in innate system's dendritic cells and macrophages and in adaptive system's B cells, highlighting how location regulates TLR function.

Figure 1. Trafficking of intracellular TLRs to endolysosomes

UNC93B physically interacts with the transmembrane domain of intracellular nucleotide-sensing TLRs, TLR7 and TLR9 in the endoplasmic reticulum. UNC93B1 regulates the trafficking of TLR7 and TLR9 to the endolysosomes upon stimulation with ssRNA or DNA.

Figure 2. Compartmentalized signaling of TLR4

TLR4 binds to LPS-MD2 complexes and engages MyD88- TIRAP adaptors at the cell surface leading to activation of early MAP kinase pathway. TLR4-LPS complex is endocytosed through a dynamin-dependent pathway terminating the MyD88-TIRAP signaling. TLR4-LPS complex within the endosome initiates a second phase of signaling by engaging TRAM-TRIF adaptors that leads to the production of interferon-β.

Figure 3. Synergistic responses of BCR and TLR9 in B cells to DNA-containing antigens

Crosslinking of BCR through DNA-containing antigens, initiates signaling resulting in the recruitment of TLR9 from endosomes to the autophagosomes in a PLD-dependent manner. TLR9 colocalizes with internalized antigen-BCR complexes within the autophagosomes and initiate synergistic signaling to NF-κB activation and MAP kinase phosphorylation.