TLR3

TLR3 Full Name

Toll-like receptor 3

TLR3 Introduction

TLR3 is an important PRR of the innate immune system. It is mainly localized in intracellular endosomes. TLR3's most common and well-studied ligand is the PAMP dsRNA produced during viral replication. As such, TLR3 is known to be the trigger for the antiviral response in the body. TLR3 senses its ligand dsRNA, then changes conformation and dimerizes to recruit its sole downstream adaptor: TIR-domain-containing adapter-inducing interferon-β (TRIF). The recruitment of TRIF is the hub of the TLR3 signaling pathway and leads to two major downstream signaling cascades. In the pathway shown, TRIF recruits TRAF3 which leads to the activation of the TBK1 and IKKε kinase complex. The kinase complex then phosphorylates and activates the transcription factor IRF3. Activated IRF3 translocates to the nucleus and strongly induces the production of type I interferons (IFN-α/β). This is a central step in the generation of an effective antiviral state. In the other signaling pathway, TRIF recruits TRAF6 and RIP1, which activates the NF-κB signaling pathway. This, in turn, induces the expression of various pro-inflammatory cytokines (e.g. TNF-α, IL-6) and chemokines to recruit and activate other immune cells to collectively clear the pathogen.

Figure 1. Mechanism of the TLR3-Toll-interleukin-1 receptor (TIR)-domain-containing adaptorinducing interferon-β (IFN-β) (TRIF) signaling pathway and structure of human TRIF. (Source: Chen Y, et al. 2021)

TLR3 plays a critical yet highly complex role in the pathophysiology of various viral diseases. On one hand, a fully functional TLR3 pathway is fundamental for defense against specific viral infections. The most well-studied is the TLR3 involvement in defense against herpes simplex encephalitis (HSE). There are a lot of studies showing that genetic defects in the genes coding TLR3 or crucial proteins of its signaling pathway (TRIF, UNC93B1, etc.) in humans greatly increase the risk of developing encephalitis due to HSV-1 infection. This allows concluding that the TLR3-mediated type I interferon response is necessary for the regulation of HSV-1 replication in the CNS. In addition, it is currently believed that TLR3, expressed on the surface of respiratory epithelial cells, is one of the most important receptors for recognition of SARS-CoV-2 in the early period of COVID-19 and triggering of innate immune defenses against the virus. On the other hand, TLR3-mediated immune response does not always have a protective effect for the host. In this case, its involvement can be a "double-edged sword." For example, the role of TLR3 in the pathogenesis of influenza virus infection is controversial. On the one hand, it is shown to help eliminate the virus, but on the other hand, hyperactivation of TLR3 is also known to cause "cytokine storm" and severe inflammatory responses leading to severe lung tissue damage and pathological consequences.

TLR3 is one of the most recent targets discovered in cancer immunotherapy. As a rule, TLR3 is used in agonists to "mimic" viral infection and activate antitumor immune responses. TLR3 agonists work by activating TLR3 on the antigen-presenting cells (APC) such as dendritic cells in the tumor microenvironment. This leads to a marked increase in the production of type I interferons, which increases NK cell cytotoxicity and the activation and infiltration of tumor-specific CTLs, which, in turn, kill tumor cells through immune mechanisms.

Alternate Names for TLR3

TLR3; toll-like receptor 3; CD283; IIAE2

• 1. Chen Y, et al. Toll-like receptor 3 (TLR3) regulation mechanisms and roles in antiviral innate immune responses. J Zhejiang Univ Sci B. 2021 Aug 15;22(8):609-632.
  2. Le Naour J, et al. Trial watch: TLR3 agonists in cancer therapy. Oncoimmunology. 2020 Jun 2;9(1):1771143.