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Toll-Like Receptors

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In 1985, Christiane Nüsslein-Volhard discovered a set of genes that established Drosophila fruit fly embryonic development and dorsal-ventral axis. Nüsslein-Volhard exclaimed “Das ist ja Toll!” upon her discovery, which roughly translates from German to ‘That is amazing’ or ‘That is great!’ The Toll gene bore a resemblance to the IL-1 Receptor, the receptor for a potent pyrogen. Scientists then began to wonder whether Toll was involved with innate immunity. In 1996, Bruno Lemaitre et al. showed that Toll-deficient flies succumbed to fungal infection. Since then, Toll-Like Receptors (TLRs) have been discovered in mammals (fish, frogs, and invertebrates have their own specific TLRs and even plants and bacteria contain basic building blocks resembling TLR defenses).

TLRs play a vital role in innate immunity and are expressed on a variety of cell types. These proteins are known as pattern recognition receptors and help detect bacteria, fungi, protozoa, and viruses. TLR activation leads to a wide range of effects, including inflammation, complement activation, and phagocytosis.

It should be noted that the study of TLR expression has been difficult for several reasons: First, TLR detection is typically based on mRNA expression, due to limitations of available antibodies. Second, TLR gene expression does not necessarily guarantee responsiveness to its corresponding ligands. Third, TLR analysis can be further complicated if the ‘purified’ cells contain contaminating populations. Despite these limitations, it is vitally important to understand TLR expression and the role they play as an innate defense mechanism against microbial threats.
TLR Accessory Molecules Cellular Location Ligands Adaptor Proteins Distribution (Mice) Distribution (Human)
 
TLR1 GRP94, PRAT4A Plasma Membrane Multiple triacylated lipopeptides MyD88, MAL/TIRAP Macrophages, Mast cells, mDCs, pDCs, T cells, Tregs B cellsǂ, Endothelial cells, Mast cells, Macrophages, MoDCs, Monocytes, T cellsǂ
TLR2 CD14, CD36, GRP94, PRAT4A Plasma Membrane Multiple glycolipids, lipopeptides, lipoproteins MyD88, MAL/TIRAP B cells, Endothelial cellsǂ, Intestinal epithelial cellsǂ, Macrophages, Mast cells, mDCs, pDCs, Monocytesǂ, T cells, Tregs subsets of B cells, Endothelial cells, Intestinal epithelial cellsǂ, Mast cells, Macrophages, mDCs, MoDCs, pDCs, Monocytesǂ, T cellsǂ
TLR4 CD14, CD36, GRP94, MD2, PRAT4A, TRIL Plasma Membrane LPS, heat shock proteins, fibrinogen MyD88, TRIF, TRAM, MAL/TIRAP Endothelial cellsǂ, Intestinal epithelial cellsǂ, Macrophages, Mast cells, B cells, mDCs, pDCs, Monocytesǂ, Tregs Endothelial cells, Intestinal epithelial cellsǂ, Mast cells, Macrophages, mDCs, MoDCs, pDCs, Monocytesǂ, T cellsǂ
TLR5 ? Plasma Membrane Flagellin MyD88 Intestinal epithelial cellsǂ, Macrophages, Mast cells, Tregs Endothelial cells, Intestinal epithelial cellsǂ, Macrophages, Mast cells, mDCs, MoDCs, Monocytes, T cells
TLR6 CD36 Plasma Membrane Multiple diacyl lipopeptides MyD88, MAL/TIRAP Intestinal epithelial cells, Macrophages, Mast cells, mDCs, pDCs, T cells, Tregs Endothelial cells, Macrophages, Mast cells, B cellsǂ, mDCs, Monocytes
TLR7 Cathepsins*, AEP*, CD14, HMGB1*, LL37*, UNC93B1, Endosome ssRNA MyD88 Intestinal epithelial cells, B cells, Macrophages, Mast cells, T cells, pDCs, Tregs B cellsǂ, Macrophages, Mast cells, mDCs, pDCs, T cells
TLR8 CD14, UNC93B1 Endosome ssRNA (human), imidazoquinoline, poly T oligonucleotides (mouse) MyD88 Intestinal epithelial cells, Macrophages, mDCs, Tregs Macrophages, mDCs, Monocytes
TLR9 AEP, AP3, Cathepsins CD14, GRP94, HMGB1, LL37*, PRAT4A, Progranulin, UNC93B1, Endosome Unmethylated CpG DNA, haemozoin MyD88 B cells, Macrophages, Mast cells, mDCs, pDCs, T cells B cellsǂ, Endothelial cells, Macrophages, Mast cells, pDCs, T cellsǂ
TLR10 (Human) ? Plasma Membrane ? MyD88 - Macrophages, B cellsǂ,
TLR11 (Mouse) ? Plasma Membrane Profilin MyD88 DCs, Bladder epithelial cells, Intestinal epithelial cells, Macrophages, Neuronsǂ -
TLR12 (Mouse) ? Plasma Membrane Profilin MyD88 DCs, Macrophages, Neuronsǂ -
TLR13 (Mouse) UNC93B1 Endosome Bacterial 23S Ribosomal RNA Sequence MyD88, TAK-1 Astrocytes, DCs, Endothelial cells of pial blood vessels, Ependymal cells, Macrophages, Neuronsǂ -

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To view full names/descriptions, mouse over any of the terms on the table.
* Still under investigation
ǂ Confirmed at the protein level

References:

 

1. Cole, J.E., et al. 2010. Mediators Inflamm. 2010:393946 (Distribution of TLRs)

2. Weissmann, G. 2010. FASEB J. 24:2137 (Origin story of Toll)

3. Lee, C.C. 2012. Nat. Rev. Immunol. 12:168 (TLR Accessory Molecules)

4. Beutler, B.A. 2009. Blood. (TLR Ligands, Adaptor Proteins)

5. Zhang, D. et al. 2004. Science. 303:1522. (TLR11)

6. Koblansky, A.A. et al. 2013. Immunity. 38:119. (TLR12)

7. Li, X.D., and Chen, Z.J. 2012. eLife. 1:e00102. (TLR13)

8. Zhongcheng, S. et al. 2011. J. Biol. Chem. 286:4517. (TLR13 Adaptor Proteins)

9. Mishra, B.B. et al. 2008. J. Neuroinflammation. 5:53. (TLR11-13 Neural Expression)

10. Pegu, A. et al. 2008. J. Immunol. 180:3399. (Human Endothelial Cell TLR Expression)

11. Fan, J. et al. 2003. J. Clin. Invest. 112:1234. (Mouse Endothelial Cell TLR Expression)

12. Renshaw, M. et al. 2002. J. Immunol. 169: 4697. (Mouse Macrophage TLR Expression)

13. Zhou, Y. et al. 2010. Immunology. 131:40. (Human Macrophage TLR Expression)

14. Cervantes, J.L. et al. 2012. Cell. Mol. Immunol. 9:434 (Mouse TLR8 Ligands)

 
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