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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.
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| 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 |
| TLR3 |
Cathepsins*, HMGB1*, TRIL, UNC93B1 |
Endosome |
dsRNA |
TRIF |
Intestinal epithelial cells, Macrophages, Mast cells, CD8+ mDCs, T cells |
Endothelial cells, Intestinal epithelial cellsǂ, Mast cells, Macrophages, mDCs, MoDCs, T cells |
| 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, Monocytes, 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 |
- |
To view full names/descriptions, mouse over any of the terms on the table.
* Still under investigation
ǂ Confirmed at the protein level |
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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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