Tlr3- Cluster of Differentiation 283

Toll-like receptor 3 (TLR3) often designated as CD283 (cluster of differentiation 283) is a type I transmembrane receptor protein. It belongs to a family of evolutionary conserved innate immune recognition molecules and recognizes double-stranded RNA, a molecular pattern associated with viral infections. Like all other members of the TLR family, TLR3 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 transmembrane domain consists of a single alpha-helix spanning the membrane, while the TIR domain is made up of a five-stranded beta-sheet surrounded by five alpha-helices. The human TLR3 ectodomain structure at 2.1 angstroms reveals a large horseshoe-shaped solenoid assembled from 23 LRRs (1). The TLR3 gene maps to chromosome 4q35 and its sequence encodes a putative 904 amino acid protein and a calculated molecular weight of 97 kDa. TLR3 is most closely related to TLR5, TLR7, and TLR8, each with 26% overall amino acid sequence identity. In vivo, two different sized transcripts for TLR3 are observed suggesting that the mRNA is alternatively spliced to generate two different forms of the protein.

TLR3 mRNA is expressed at highest levels in placenta and pancreas. There are conflicting reports regarding the expression of TLR3 in particular leukocyte populations. Some suggest that TLR3 is only expressed by dendritic cells while others find that TLR3 is expressed by T or NK cells. In vitro, PMA-differentiated THP-1 TLR3 is moderately upregulated by autocrine IFN-?, IL-1ß, IL-6, IL-10, and TNF-?. Further, TLR3 mRNA is elevated after exposure to Gram-negative bacteria and to an even greater extent in response to Gram-positive bacteria. Ex vivo, TLR3 expression is elevated in both monocytes and granulocytes upon exposure to Gram-negative bacteria. TLR3 is usually localized intracellularly, perhaps to the lysosomal compartment or at the cell surface. However the localization of TLR3 is cell type dependent.

Human TLR3 recognizes foreign-derived double-stranded RNA of certain viruses like influenza, endogenous necrotic cell RNA and polyinosinic acid as ligands. Stimulation of the receptor by the ligand induces the activation of NF-kappaB and the production of type I interferons (IFNs) which signal other cells to increase their antiviral defenses (2). TLR3 relies on a TIR domain-containing adaptor inducing IFN-beta (TRIF)-mediated pathway for the production of IFN- in response to pathogen recognition. Trif contains a RIP homotypic interaction motif (RHIM) at the C terminus that is essential for binding of RIP1 and RIP3, two serine-threonine kinases linked to tumor necrosis factor (TNF)?mediated NF- B activation. (3, 4, 5). Activation of TLR3 leads to recruitment of receptor-interacting protein 1, TRAF3 and TRAF6, which activates TRAF family member-associated NF- B activator-binding kinase 1 (TBK1) andr inducible I B kinase (IKK-i), which directly phosphorylate IRF3 and IRF7 for the production of type-I IFN cytokines.(6)

TLR3 has been implicated in various viral infections of the respiratory tract and in central nervous system (CNS) diseases. On the contrary it positively contributes to the immune response to invading encephalomyocarditis virus. TLR3 has also been implicated in the protection against herpes simplex virus type 2 infection of the female genital tract. Recent work on TLR3 reveals its role in the immunobiology of skeletal muscle (7).

Reference:

1. J Endotoxin Res. 2006; 12(6):375-8

2. Nature. 2001 Oct 18; 413(6857):732-8

3. Nature Immunology 5, 503 - 507 (2004)

4.Rock, F.L. et al. (1998) Proc. Natl. Acad. Sci. USA 95:588.

5. Science. 2005 Jul 22; 309(5734):581-5. Epub 2005 Jun 16

6.Oncogene (2008) 27, 181–189; doi:10.1038/sj.onc.1210906

7. Clinical Microbiology Reviews, January 2008, p. 13-25, Vol. 21, No. 1