Pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs) conserved structures expressed by microbial pathogens. PRRs can be broadly categorized into secreted, transmembrane, and cytosolic classes. The transmembrane PRRs include the Toll-like receptor (TLR) family, which is either expressed on the plasma membrane or in endosomal/lysosomal organelles. Intracellular TLRs (TLR3, TLR7, and TLR9) mainly detect microbial nucleic acids and also sense endogenous ligands or DAMPs for damage-associated molecular patterns, such as self-DNA released, for example, during self-tissue damage, or cancer cell death. Intracellular TLRs are highly expressed in antigen-presenting cells (APCs) such as dendritic cells (DCs) and macrophages that constitutively express major histocompatibility complex class-II (MHCII) molecules. In DCs, antigen presentation coupled to TLR activation induces their maturation through the expression of co-stimulatory molecules, chemokine receptors, and cytokine production. Maturation makes DCs immunogenic, whereas the absence of TLR signals leads to tolerance. Several lines of evidence link intracellular TLR signaling and antigen presentation. First, activation of TLR in DCs and macrophages regulates several steps of antigen presentation, such as antigen uptake and phagosomal maturation 1, 2••. Next, TLR activation stimulates tubulation of endolysosomes in DCs containing MHCII-peptide complexes facilitating their delivery to the plasma membrane 3••, 4. Finally, seminal work shows that TLR activation in DCs targets antigens in the lysosomal compartment, a site for processing of the MHCII chaperone, the invariant chain (Ii) [5]. MHCII molecules require Ii for their folding and trafficking. Similarly, intracellular TLRs associate with the chaperone molecule UNC93B1 that helps their folding and trafficking to endosomal compartments for cleavage by proteases and activation 6••, 7••, 8••, 9••, 10••.

Thus, several features of intracellular TLRs, such as folding, trafficking, and processing in APCs, are shared with MHCII molecules.

Here, we will discuss how intracellular TLRs utilize the antigen processing machinery, mainly in DCs, for their optimal trafficking and activation, resulting in enhanced antigen presentation. We will start with the identification of proteases required for their cleavage and activation. Then, we will highlight the role of the chaperone molecule, UNC93B1, in their folding and endosomal trafficking. Finally, we will discuss the nature of the endolysosomal compartments they reached for optimum specific cytokine response.