Toll-Like Receptors

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	-

No Results Found. Please try a different configuration.

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

Human and Mouse Antibody Products
Human Specificity	Clone
TLR1 (CD281)	TLR1.136
TLR2 (CD282)	QA16A01, TL2.1, W15145C
TLR3 (CD283)	TLR-104
TLR4 (CD284)	HTA125
TLR5 (CD285)	S16021I
TLR6 (CD286)	TLR6.127
TLR8 (CD288)	S16018A
TLR9 (CD289)	S16013D
TLR10 (CD290)	3C10C5
MyD88	O91B8
Mouse Specificity	Clone
TLR2 (CD282)	CB225, QA16A01
TLR3 (CD283)	11F8
TLR4 (CD284)	SA15-21
TLR4 (CD284)/MD2 Complex	MTS510
TLR5 (CD285)	ACT5

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)