Tlr8- Cluster of Differentiation 288

Toll-like receptor 8 (TLR8) often designated as CD288 (cluster of differentiation 288) is a member of evolutionarily conserved Toll-like receptor family which are critical parts of the evolutionarily conserved innate immune system. TLR8 has been identified as natural receptor for single-stranded RNA, and is thought to act as potent activator of innate immune responses upon viral infections. Like all other members of the TLR family, TLR8 is composed of an extracellular domain containing multiple leucine-rich repeats (LRRs), a transmembrane region, and a cytoplasmic tail containing the conserved TIR domain. The TLR8 sequence encodes a 1041 amino acid protein containing 26 N-terminal leucine rich repeats with a calculated molecular weight of 120 kDa. The gene for TLR8 has been mapped to chromosome Xp22. TLR8 is most closely related to TLR7 and TLR9 with 43% and 35% overall amino acid sequence identity, respectively and together they constitute one of the six major TLR clades. (1,2)

In vivo, TLR8 mRNA is expressed in lung, placenta, spleen, lymph node, bone marrow, and PBLs, with highest expression found in monocytes. In vitro, TLR8 mRNA expression is upregulated in THP-1 cells upon PMA-induced differentiation. TLR8 is highly upregulated by autocrine IL-1?, IL-6, IL-10, and TNF-?, and is even more enhanced by exposure to IFN-?. TLR8 mRNA expression in THP-1 cells is elevated after exposure to both Gram-positive and Gram-negative bacteria. Ex vivo, monocyte TLR8 expression increases while granulocyte expression decreases on exposure to Gram-negative bacteria. (3) Like TLR7 and TLR7, TLR8 is exclusively localized to intracellular

compartments like endosomes, suggesting that these intracellular TLRs recognize

nucleic acids following the internalization and lysing of viruses.

Human TLR8 preferentially mediates the recognition of human immunodeficiency virus, vesicular stomatitis virus, and influenza virus-derived guanosine or uridine rich ss RNA and a synthetic compound (imidazoquinoline compound R848) with antiviral activity R-848. Following nucleic acid recognition, TLR8 recruit the TIR-domain containing adapter called MyD88. MyD88 forms a complex with members of IRAK family (IRAK1 and IRAK4) and TRAF6, which in turn activates TAK1 and results in the activation of NF-?B and synthesis of type I interferons.(4)

A novel role for TLR8 as a suppressor of neurite outgrowth as well as an inducer of neuronal apoptosis has been found. Reports suggest that TLR8 functions in neurons through an NF-kappaB-independent mechanism (5). Recent studies also reveal that the human TLR8 signaling pathway is essential for reversing the function of Treg cells that play a critical role in suppressing immune responses and inducing immune tolerance to cancer and infectious diseases. Thus, the combination of peptide-based vaccines with a TLR8 agonist, may greatly improve the therapeutic potential of cancer vaccines. (4)

Reference:

1. Chuang, T.H. & R.J. Ulevitch (2000) Eur. Cytokine Netw. 11:372.

2. Dunne, A. & L.A.J. O'Neill (2003) Sci. STKE 2003:re3.

3. Heine, H. & E. Lein (2003) Int. Arch. Allergy Immunol. 130:180.

4. Oncogene (2008) 27, 190–199; doi:10.1038/sj.onc.1210913

5. Cell Cycle. 2007 Sep;6(23):2859-68. Epub 2007 Sep 4