TLR9

TLR9, or Toll-like receptor 9, is a pattern recognition receptor of the innate immune system and a member of the Toll-like receptor family. In humans, TLR9 is expressed mainly in endosomal compartments of plasmacytoid dendritic cells, conventional dendritic cells, B cells, and some monocytes. The receptor traffics from the endoplasmic reticulum to endolysosomal compartments with the help of trafficking proteins such as UNC93B1.

TLR9 recognizes unmethylated CpG motifs that are abundant in bacterial and viral DNA. Activation requires DNA uptake into endosomes and is inhibited by methylation of CpG dinucleotides in vertebrate DNA.

Upon ligand binding, TLR9 signals through the adaptor protein MyD88, recruiting IRAK kinases and culminating in activation of NF-κB and IRF7. This leads to transcription of pro-inflammatory cytokines (for example, TNF, IL-6, IL-12) and type I interferons (notably IFN-α) with prominent production in plasmacytoid dendritic cells. The cytokine milieu promotes maturation of antigen-presenting cells and links innate and adaptive immunity.

Clinical relevance: dysregulated TLR9 signaling can contribute to autoimmune diseases such as systemic lupus erythematosus, due to recognition of self-DNA. Conversely, TLR9 agonists, particularly CpG-containing oligodeoxynucleotides, have been explored as vaccine adjuvants and immunotherapies in cancer and infectious diseases.

Regulation and pharmacology: endosomal acidification is required for TLR9 signaling; agents that raise endosomal pH, such as chloroquine and hydroxychloroquine, can dampen TLR9 responses.

Genetic variation in TLR9 has been associated with differences in infection susceptibility and autoimmune risk in various populations.