Toll-like Receptor - Activation and Effects

Activation and Effects

Following activation by ligands of microbial origin, several reactions are possible. Immune cells can produce signalling factors called cytokines, which trigger inflammation. In the case of a bacterial factor, the pathogen might be phagocytosed and digested, and its antigens presented to CD4+ T cells. In the case of a viral factor, the infected cell may shut off its protein synthesis and may undergo programmed cell death (apoptosis). Immune cells that have detected a virus may also release anti-viral factors such as interferons.

The discovery of the Toll-like receptors finally identified the innate immune receptors that are responsible for many of the innate immune functions that had been studied for many years. It is interesting to note that TLRs seem to be involved only in the cytokine production and cellular activation in response to microbes, and do not play a significant role in the adhesion and phagocytosis of microorganisms.

Schmidt et al. demonstrated that TLR4 is involved in the development of contact allergy to nickel in humans. By binding to two non-conserved histidines, H456 and H458, Ni2+ cross-links the two receptor monomers, TLR4, and MD2, triggering formation of a dimer that structurally resembles the one induced by Lipopolysaccharide. That, in turn, activates the proinflammatory intracellular signal transduction cascades.

Said et al. showed that TLR ligands cause an IL-10-dependent inhibition of CD4 T-cell expansion and function by up-regulating PD-1 levels on monocytes, which leads to IL-10 production by monocytes after binding of PD-1 by PD-L.

Toll-like receptors have also been shown to be an important link between innate and adaptive immunity through their presence in dendritic cells. The TLRs 3 and 4 are present on the surface of monocyte derived dendritic cells and use the Myd88-dependent pathway to produce interleukins 12 and 18 which signal naive T-cells to mature into type 1 helper T cells. These TLRs also use the TIRF pathway to upregulate costimulatory proteins which aid in the differentiation of T-cells. TLRs 7 and 9 are present on the endosome of plasmacytoid dendritic cells. These proteins solely make use of the Myd88 dependent pathway to produce interleukins for the maturation of naive T-cells to type 1 helper T-cells.

Evelyn A. Kurt-Jones et al. also demonstrated TLR4s role in the innate immune response to the respiratory syncytial virus. Cytokine production increased upon exposing human monocytes to RSV. After knocking out CD14, TLR4's coactivator, this response was significantly diminished, as were the responses in C3H/HeJ mice, a mouse strain with reduced immune responses, and mice deficient in TLR4.