TLRs and Immune Function

Interest in TLRs as being important elements of innate immune function in mammals was initiated by the discovery that the Lps gene, which had been identified by

TABLE 10.1

Microbial and Endogenous TLR Ligands

Microbial Ligands

Triacylated lipopeptidesa Peptidoglycan, lipoteichoic acid, lipoarabinomannan, and porinsb Diacylated lipopeptidese dsRNAf LPSg

TLR1 and TLR2 TLR2

TLR2 and TLR6

TLR3

TLR4

Endogenous Ligands

HSP70 and GP96c,d

HSP60, HSP70, GP96, hyaluronan, lung surfactant protein A, fibronectin, fibrinogen, heparan sulfate, and P-defensin 2h

TLR5 TLR7

TLRS

TLR9

TLR10

TLR11

TLR12

TLR13

Flagellin'

Guanosine- or uridine-rich ssRNAj-k Guanosine- or uridine-rich ssRNAj-k Unmethylated CpG DNA1 Unknown

T. gondii profilin-like proteinn

Unknown

Unknown

Chromatin-IgG complexes"

Sources: a. Takeuchi, O., Sato, S., Horiuchi, T., Hoshino, K., Takeda, K., Dong, Z., Modlin, R. L., and Akira, S. Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J Immunol 169 (1), 10-14, 2002. b. Miyake, K. Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Semin Immunol 19 (1), 3-10, 2007. c. Vabulas, R. M., Ahmad-Nejad, P., Ghose, S., Kirschning, C. J., Issels, R. D., and Wagner, H. HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J Biol Chem 277 (17), 15107-12, 2002. d. Vabulas, R. M., Braedel, S., Hilf, N., Singh-Jasuja, H., Herter, S., Ahmad-Nejad, P., Kirschning, C. J., Da Costa, C., Rammensee, H. G., Wagner, H., and Schild, H. The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Toll-like receptor 2/4 pathway. J Biol Chem 277 (23), 20847-53, 2002. e. Buwitt-Beckmann, U., Heine, H., Wiesmuller, K. H., Jung, G., Brock, R., Akira, S., and Ulmer, A. J. TLR1- and TLR6-independent recognition of bacterial lipopeptides. J Biol Chem 281 (14), 904957, 2006. f. Alexopoulou, L., Holt, A. C., Medzhitov, R., and Flavell, R. A. Recognition of double-stranded RNA and activation of NF-kappaB by Toll- like receptor 3. Nature 413 (6857), 732-78, 2001.

g. Poltorak, A., He, X., Smirnova, I., Liu, M. Y., Huffel, C. V., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., Freudenberg, M., Ricciardi-Castagnoli, P., Layton, B., and Beutler, B. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282 (5396), 2085-8, 1998.

h. Beg, A. A. Endogenous ligands of Toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol 23 (11), 509-12, 2002. i. Hayashi, F., Smith, K. D., Ozinsky, A., Hawn, T. R., Yi, E. C., Goodlett, D. R., Eng, J. K., Akira, S., Underhill, D. M., and Aderem, A. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410 (6832), 1099-103, 2001. j. Sioud, M. Single-stranded small interfering RNA are more immunostimulatory than their double-stranded counterparts: a central role for 2'-hydroxyl uridines in immune responses. Eur J Immunol 36 (5), 1222-30, 2006. k. Lee, J., Chuang, T. H., Redecke, V., She, L., Pitha, P. M., Carson, D. A., Raz, E., and Cottam, H. B. Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7. Proc Natl Acad Sci USA 8, 8, 2003. l. Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Wagner, H., Takeda, K., and Akira, S. A Toll-like receptor recognizes bacterial DNA. Nature 408 (6813), 740-45, 2000. m. Leadbet-ter, E. A., Rifkin, I. R., Hohlbaum, A. M., Beaudette, B. C., Shlomchik, M. J., and Marshak-Rothstein, A. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416 (6881), 603-7, 2002. n. Yarovinsky, F., Zhang, D., Andersen, J. F., Bannenberg, G. L., Serhan, C. N., Hayden, M. S., Hieny, S., Sutterwala, F. S., Flavell, R. A., Ghosh, S., and Sher, A. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308 (5728), 1626-9, 2005._

gene mapping as being responsible for the resistance to lethal endotoxin or bacterial LPS challenge in mice, encoded TLR4.17 Mice with natural mutations in the Tlr4 gene did not respond to E. coli LPS or Lipid A, the portion of the LPS molecule responsible for its biological activity. It was subsequently shown that cells from genetically engineered Tlr4 gene-deficient mice did not respond to LPS stimulation, confirming that TLR4 was indeed the signaling receptor for LPS.18 Medzhitov and Janeway subsequently showed that TLR4 provides an inflammatory adjuvant signal needed to evoke CD4 T cell responses, suggesting that TLRs also play an important role in regulating adaptive immune responses.19

While this early work focused primarily on TLR4 and innate immune cell responses, the rapid discovery of TLR family members revealed that TLRs have specialized functions depending on their cellular distribution. It is now known that many different cell types express TLRs. However, it is clear that they are more widely expressed on innate immune cell types, including monocytes, macrophages, neutrophils, and dendritic cells. Their primary function on these immune cells is to act as PRRs for microbial PAMPs in the infected host. Once triggered, TLR signaling leads to the rapid production of proinflammatory cytokines, including those needed for effective control of bacterial and viral infections such as type 1 and 2 interferons (IFNs).20,21 Another well-described function for TLRs is their ability to transform resting innate cell types, like dendritic cells, into potent antigen-presenting cells (APCs). This occurs via upregulation of co-stimulatory receptors such as CD80, CD86, and CD40 that are needed to promote CD4 and CD8 T cell activa-tion.22-27 In addition, TLR signaling induces the production of interleukin-12 (IL-12), IL-6, IL-10, transforming growth factor-P (TGFP), IFN-a, and IFN-P by APCs, which help guide the differentiation of naive CD4 T cells into T helper cell subsets.28-31 Thus, TLR signaling promotes a rapid inflammatory response, which then leads to the development of effective adaptive immune system reactivity.

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