The Functional Effects of Physical Interactions among Toll-like Receptors 7, 8, and 9

Abstract

Toll-like receptors (TLRs) TLR1, TLR2, TLR4, and TLR6 are evolutionarily conserved, highly homologous, and localized to plasma membranes of host cells and recognize pathogen-associated molecular patterns (PAMPs) derived from bacterial membranes. These receptors cooperate in a pairwise combination to elicit or inhibit the inflammatory signals in response to certain PAMPs. The other TLRs that are evolutionarily closely related and highly homologous are TLR7, TLR8, and TLR9. They are all confined to the membranes of endosomes and recognize similar molecular structures, the oligonucleotide-based PAMPs. However, the cooperative interactions among these receptors that may modulate the inflammatory signaling in response to their cognate agonists are not reported. We report here for the first time the functional effects of one TLR on the other among TLR7, TLR8, and TLR9. The results indicate that TLR8 inhibits TLR7 and TLR9, and TLR9 inhibits TLR7 but not vice versa in HEK293 cells transfected with TLRs in a pairwise combination. This is concluded by selectively activating one TLR over the other by using small molecule TLR agonists. We also show that these inhibitory interactions are the result of direct or indirect physical interactions between the TLRs. The murine TLR8 that does not respond to any known human TLR8 agonists also inhibits both murine and human TLR7. The implications of the inhibitory interactions among these TLRs in host-pathogen recognition and subsequent inflammatory responses are not obvious. However, given the complexity in expression pattern in a particular cell type and the variation in distribution and response to different pathogens and stress signals in different cell types, the inhibitory physical interactions among these TLRs may play a role in balancing the inflammatory outcome from a given cell type to a specific challenge. Toll-like receptors (TLRs) TLR1, TLR2, TLR4, and TLR6 are evolutionarily conserved, highly homologous, and localized to plasma membranes of host cells and recognize pathogen-associated molecular patterns (PAMPs) derived from bacterial membranes. These receptors cooperate in a pairwise combination to elicit or inhibit the inflammatory signals in response to certain PAMPs. The other TLRs that are evolutionarily closely related and highly homologous are TLR7, TLR8, and TLR9. They are all confined to the membranes of endosomes and recognize similar molecular structures, the oligonucleotide-based PAMPs. However, the cooperative interactions among these receptors that may modulate the inflammatory signaling in response to their cognate agonists are not reported. We report here for the first time the functional effects of one TLR on the other among TLR7, TLR8, and TLR9. The results indicate that TLR8 inhibits TLR7 and TLR9, and TLR9 inhibits TLR7 but not vice versa in HEK293 cells transfected with TLRs in a pairwise combination. This is concluded by selectively activating one TLR over the other by using small molecule TLR agonists. We also show that these inhibitory interactions are the result of direct or indirect physical interactions between the TLRs. The murine TLR8 that does not respond to any known human TLR8 agonists also inhibits both murine and human TLR7. The implications of the inhibitory interactions among these TLRs in host-pathogen recognition and subsequent inflammatory responses are not obvious. However, given the complexity in expression pattern in a particular cell type and the variation in distribution and response to different pathogens and stress signals in different cell types, the inhibitory physical interactions among these TLRs may play a role in balancing the inflammatory outcome from a given cell type to a specific challenge. In vertebrates the innate immune system is a first line of defense against invading agents (1Janeway Jr., C.A. Medzhitov R. Annu. Rev. Immunol. 2002; 20: 197-216Crossref PubMed Scopus (6247) Google Scholar). The innate immune system contains components conserved between vertebrates and invertebrates and includes receptors recognizing molecular structures that are highly conserved among pathogens called pathogen-associated molecular patterns (PAMPs). 2The abbreviations used are: PAMP, pathogen-associated molecular pattern; TLR, Toll-like receptor; NF-κB, nuclear factor-κB; IP, immunoprecipitation; EGFP, enhanced green fluorescent protein; CFP, cyan fluorescent protein; HA, hemagglutinin; PBMCs, peripheral blood mononuclear cells; mDCs, myeloid dendritic cells; pDCs, plasmacytoid dendritic cells; PMA, phorbol ester 12-myristate 13-acetate; m, murine; h, human; LPS, lipopolysaccharide. Activation of the innate immune system through pattern recognition receptors by molecules derived from evolutionarily distant pathogens like bacteria, fungi, and viruses provides the necessary signals for the initiation and activation of the adaptive immune response. Thus, the innate immune system plays a critical role in triggering the activation of adaptive immune responses by promoting the presentation of antigens and up-regulation of various cytokines and co-stimulatory molecules (2Barton G.M. Medzhitov R. Curr. Opin. Immunol. 2002; 14: 380-383Crossref PubMed Scopus (292) Google Scholar). Toll-like receptors (TLRs), mammalian homologs of the Drosophila receptor Toll, are an integral part of the innate immune system (1Janeway Jr., C.A. Medzhitov R. Annu. Rev. Immunol. 2002; 20: 197-216Crossref PubMed Scopus (6247) Google Scholar, 3Takeda K. Kaisho T. Akira S. Annu. Rev. Immunol. 2003; 21: 335-376Crossref PubMed Scopus (4772) Google Scholar). So far 10 different human TLRs (TLR1 to 10) have been identified (4Medzhitov R. Janeway C.J. Cell. 1997; 91: 295-298Abstract Full Text Full Text PDF PubMed Scopus (1985) Google Scholar). All TLRs are type I transmembrane proteins composed of an N-terminal extracellular domain with leucinerich repeats involved in ligand (PAMP) recognition, a single transmembrane domain, and a cytoplasmic domain largely made up of a TIR (Toll/IL-1 receptor homology) domain required for downstream signaling (5Medzhitov R. Nat. Rev. Immunol. 2001; 1: 135-145Crossref PubMed Scopus (3284) Google Scholar, 6Akira S. Adv. Immunol. 2001; 78: 1-56Crossref PubMed Scopus (298) Google Scholar). While TLR1, -2, and -4–6 are involved in recognizing PAMPs associated with bacterial membranes (1Janeway Jr., C.A. Medzhitov R. Annu. Rev. Immunol. 2002; 20: 197-216Crossref PubMed Scopus (6247) Google Scholar, 3Takeda K. Kaisho T. Akira S. Annu. Rev. Immunol. 2003; 21: 335-376Crossref PubMed Scopus (4772) Google Scholar), TLR3 and -7–9 recognize oligonucleotide (RNA and DNA)-based molecular patterns from both bacteria and viruses (7Diebold S.S. Kaisho T. Hemmi H. Reis e Akira S. Sousa C. Science. 2004; 303: 1529-1531Crossref PubMed Scopus (2757) Google Scholar, 9Gorden K.B. Gorski K.S. Gibson S.J. Kedl R.M. Kieper W.C. Qiu X. Tomai M.A. Alkan S. Vasilakos J.P. J. Immunol. 2005; 174: 1259-1268Crossref PubMed Scopus (585) Google Scholar). To date, the role of TLR10 has not been established, and its ligand (PAMP) has not been identified. The TLRs that recognize bacterial membrane components are confined to the plasma membrane (10O'Neill L.A.J. Science. 2004; 303: 1481-1482Crossref PubMed Scopus (71) Google Scholar). The other TLRs that recognize oligonucleotide -based ligands are distributed to the membranes of the endosomal compartment (10O'Neill L.A.J. Science. 2004; 303: 1481-1482Crossref PubMed Scopus (71) Google Scholar, 11Latz E. Schoenemeyer A. Visintin A. Fitzgerald K.A. Monks B.G. Knetter C.F. Lien E. Nilsen N.J. Espevik T. Golenbock D.T. Nat. Immun. 2004; 5: 190-198Crossref Scopus (1164) Google Scholar). Although most TLRs function as homodimers (or homopolymers) upon ligand binding, some ligands require cooperation of more than one TLR in activating the downstream signaling cascade. For example, in vitro studies using cotransfection of different TLRs into cells that normally do not express TLRs have confirmed that heterotypic interactions between TLR1 and TLR2, TLR2 and TLR6, and TLR4 and TLR6 are required for recognition and activation of signaling in response to triacyl lipopetides, diacyl lipopeptides, and other bacterial cell wall components (11Latz E. Schoenemeyer A. Visintin A. Fitzgerald K.A. Monks B.G. Knetter C.F. Lien E. Nilsen N.J. Espevik T. Golenbock D.T. Nat. Immun. 2004; 5: 190-198Crossref Scopus (1164) Google Scholar, 13Ozinsky A. Underhill D.M. Fontenot J.D. Hajjar A.M. Smith K.D. Wilson C.B. Schroeder L. Aderem A. Proc. Natl. Acad. Sci. U. S. A. 2000; 9: 13766-13771Crossref Scopus (1693) Google Scholar, 17Sandor F. Latz E. Re F. Mandell L. Repik G. Golenbock D.T. Espevik T. Kurt-Jones E.A. Finberg R.W. J. Cell Biol. 2003; 162: 1099-1110Crossref PubMed Scopus (105) Google Scholar). However, the TLR-TLR heterotypic interactions are not always activating. The heterotypic TLR1-TLR4 interactions were shown to be inhibitory to TLR4 signaling in response to lipopolysaccharide (LPS) (18Spitzer J.H. Visintin A. Mazzoni A. Kennedy M.N. Segal D.M. Eur. J. Immunol. 2002; 32: 1182-1187Crossref PubMed Scopus (46) Google Scholar). Therefore, certain heterotypic TLR-TLR interactions are essential not only for the recognition of a particular PAMP but may also play a regulatory role in controlling the of inflammatory response. The that may heterotypic interactions among TLR1, -2, and to be their distribution (10O'Neill L.A.J. Science. 2004; 303: 1481-1482Crossref PubMed Scopus (71) Google Scholar), closely related as by homology) Curr. Immunol. 2002; Google Scholar), and the and and the agonists are of bacterial of the agonists. other of TLR7, TLR8, and TLR9, are also highly homologous closely Eur. 2000; Google Scholar, X. A. Eur. 2000; Google Scholar), are in the compartment (10O'Neill L.A.J. Science. 2004; 303: 1481-1482Crossref PubMed Scopus (71) Google Scholar, 11Latz E. Schoenemeyer A. Visintin A. Fitzgerald K.A. Monks B.G. Knetter C.F. Lien E. Nilsen N.J. Espevik T. Golenbock D.T. Nat. Immun. 2004; 5: 190-198Crossref Scopus (1164) Google Scholar), and recognize oligonucleotide-based and molecular patterns as agonists. However, is or inhibitory interactions among these TLRs. or in may have these of The most are as the of agonists that selectively TLR7 or TLR8, as their cognate both the receptors (7Diebold S.S. Kaisho T. Hemmi H. Reis e Akira S. Sousa C. Science. 2004; 303: 1529-1531Crossref PubMed Scopus (2757) Google Scholar, F. Hemmi H. H. F. C. Akira S. G. H. S. Science. 2004; 303: PubMed Scopus Google G.M. Medzhitov R. Curr. Opin. Immunol. 2002; 14: 380-383Crossref PubMed Scopus (292) Google activation of TLR7 or TLR8 by of the and the innate immune system is known to have other molecular that recognize and signaling T. T. K. Akira S. T. Nat. Immun. 2004; 5: Scopus Google Scholar, Jr., E. K. T. Jr., J. 2005; PubMed Scopus Google is known the role of TLR8 in innate as is in the F. J. C. A.M. H. G. S. Nat. Immun. 2002; Scopus Google Scholar), the studies to only human cells that for any and in all the cells that express TLR7 also express TLR9 S. S. A. T. S. G. J. Immunol. 2002; PubMed Scopus Google Scholar, Immunol. 2002; 14: PubMed Scopus Google Scholar), and the activation of of these receptors to similar response F. Hemmi H. H. F. T. H. G. K. Akira S. H. S. Eur. J. Immunol. 2003; PubMed Scopus Google Scholar), the effects of any of one on the any immune or cells that express TLRs are not for of the function of one TLR in the and of the other In report the of pairwise of TLR7 and TLR8, TLR7 and TLR9, and TLR8 and TLR9 by selectively activating one TLR over the other to the functional of physical interactions among these TLRs. We of immune response that selectively TLR7 or TLR8 K.B. Gorski K.S. Gibson S.J. Kedl R.M. Kieper W.C. Qiu X. Tomai M.A. Alkan S. Vasilakos J.P. J. Immunol. 2005; 174: 1259-1268Crossref PubMed Scopus (585) Google Scholar), and K.A. D.M. W.C. J. 2001; 21: PubMed Scopus Google used as a TLR9 HEK293 cells that do not normally express any of the TLRs and are to were used in and cells transfected with were in with and and and were made by K.B. Gorski K.S. Gibson S.J. Kedl R.M. Kieper W.C. Qiu X. Tomai M.A. Alkan S. Vasilakos J.P. J. Immunol. 2005; 174: 1259-1268Crossref PubMed Scopus (585) Google Scholar). 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Gorski K.S. Gibson S.J. Kedl R.M. Kieper W.C. Qiu X. Tomai M.A. Alkan S. Vasilakos J.P. J. Immunol. 2005; 174: 1259-1268Crossref PubMed Scopus (585) Google Scholar). and of of for TLR were into cells and were with and in cell and and to the For cell were by and to membranes. with and with using For cell were with and Cell of in were with of the for by the of of the were with of The were for in and to as The immune cells that express TLRs are not to the of specific TLR-TLR functional interactions more complexity to functional interactions among TLR7, TLR8, and TLR9 as are all localized to the compartment (10O'Neill L.A.J. Science. 2004; 303: 1481-1482Crossref PubMed Scopus (71) Google and in different in different immune cells S. S. A. T. S. G. J. Immunol. 2002; PubMed Scopus Google Scholar, T. R. S. Immunol. 2002; PubMed Scopus Google Scholar, Immunol. 2002; 14: PubMed Scopus Google Scholar). of immune cells the for of the function of one TLR in the and of the other the specific studies require over the of the have used HEK293 an to the expression of one TLR over the other as do not express any of the TLRs used in and are also used for the function of TLRs in activation of TLR7 or TLR8 is the most of to the of TLR-TLR physical interactions on signaling by of the receptors are has been shown that and selectively TLR7 and TLR8, as by activation in TLR7 or TLR8 transfected HEK293 cells and in human K.B. Gorski K.S. Gibson S.J. Kedl R.M. Kieper W.C. Qiu X. Tomai M.A. Alkan S. Vasilakos J.P. J. Immunol. 2005; 174: 1259-1268Crossref PubMed Scopus (585) Google Scholar). have used and to selectively TLR7 and TLR8, and to TLR9, and the of one TLR on the signaling of the other TLR8 TLR7 and TLR9, and TLR9 human TLRs TLR8, and were in a pairwise combination in cells and selectively one of the TLRs to the of the other on the signaling by the In cotransfection of to TLR were used of In single TLR the of to that particular TLR the as in cotransfection To the similar to that in cotransfection have used the to the or the TLR2 the of of the not have any on the to the as provides a that is between single and cotransfection expression is to or than The results of pairwise cotransfection of cells by TLR expression activation of TLR7 by TLR8 by and TLR9 by that TLR8 inhibits TLR7 and TLR9 and TLR9 inhibits TLR7 the other TLR7 inhibitory effects on TLR8 or TLR9 and TLR9 not inhibit TLR8 The effects of TLR7 on the TLR9 response to were all the to in the of in response to the activation of TLRs were Therefore, always a given of and as one and as one and and as for a The of TLR7 by TLR8 more with the of TLR7 by TLR9 or TLR9 by TLR8 and The molecular for the inhibitory effects of TLR8 and TLR9 may be as for downstream signaling proteins as all these TLRs a S. R. Sci. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, Fitzgerald K.A. 2003; PubMed Scopus Google Scholar), and the and S. R. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google and direct physical as all these TLRs confined to the the these inhibitory effects are of the for the downstream signaling the of TLR8 or TLR9 with other TLRs of different compartment also have similar inhibitory To TLR8 or TLR9 were with TLR2 or in and the activation in response to or The results show that TLR8 or TLR9 does not inhibit TLR2 or TLR4 that TLR2 as in single TLR to the of similar to does not have any functional effects on TLR7, TLR8, or TLR9 Therefore, is that the inhibitory effects of TLR8 TLR7 and and TLR9 are of a direct for the downstream signaling the proteins and the are to the receptor only binding, and in these only one of the TLRs selectively Therefore, the inhibitory effects of TLR8 and TLR9 may have from direct or indirect through an physical The of TLR8 and TLR9 from or the of one TLR by the other is not a of direct for downstream signaling the other is the direct or indirect physical interactions between the TLRs. one TLR inhibits the other TLR through direct or indirect physical the of TLR7 or TLR9 by TLR8 and TLR7 by TLR9 be on the of the inhibitory To the cotransfection were by the of to the inhibitory TLR against a of to the TLR that is the of by with a activation in response to 10 TLR agonists and expression were the were not of as in HEK293 cells TLR8, have used N-terminal TLR8 for in these to the using The of TLR8 not the results as its inhibitory effects on TLR7 or TLR9 were with The results show a between of TLR8 or TLR9 from of the of TLR7 and TLR9, of The of the inhibitory TLRs in inhibitory effects The inhibitory effects of TLR8 and TLR9 are of the or of used for the activation of TLR7 or TLR9 to 10 is in The inhibitory effects of TLR8 on TLR7 as a function of of TLR8 are with more inhibitory effects of TLR8 on TLR9 or TLR9 on TLR7 These results are also with results that the of TLR7 by TLR8 is more than that of TLR9 by TLR8 or TLR7 by TLR9 in cotransfection using of to is to that the response of TLR8 to is with of is an in expression for is that the activation in response to has been of the other in TLR7 and TLR9 the of TLR7 or the activation of TLR9 is more the effects are and with expression of as a function of of TLR9 as in the the activation of TLR9 in the of TLR7 with TLR9 is that TLR7 and TLR9 interactions are to TLR9 The between expression and the inhibitory that the of one TLR by the other is of direct or indirect physical To the of physical interactions between these were on cell from cells transfected with to and or and TLR9. the subsequent with the used in of S. were not of against cell have used TLR7 with in as the the of were to on from cells with TLR7 and TLR9. The results of show using and TLR9 from the cell as on using and These results that the inhibitory effects of TLR8 or TLR9 may be to direct or indirect physical interactions between the TLRs. These interactions to be among TLR7, TLR8, and TLR9 but not TLR2 as by the of TLR2 with Although the with any or the or not show any on the the not be on of cells TLR7 and TLR9 of the on the of TLR9 However, the physical interactions by between TLR7 and TLR9 have been using on HEK293 cells and The physical of TLR8 with TLR7 or TLR9 is the of TLR7, TLR8, and TLR9 in their has been shown that plasma TLR1 and TLR2, also as and of TLR2 with TLR4 in HEK293 cells F. Latz E. Re F. Mandell L. Repik G. Golenbock D.T. Espevik T. Kurt-Jones E.A. Finberg R.W. J. Cell Biol. 2003; 162: 1099-1110Crossref PubMed Scopus (105) Google Scholar). Therefore, the and among TLRs to be an essential for recognition and activation as by may also to the regulatory or and and human TLR8 and the does not respond to any of the agonists known to human TLR8 F. J. C. A.M. H. G. S. Nat. Immun. 2002; Scopus Google Scholar). However, is that the may the inhibitory function of human Therefore, to the inhibitory of similar and were by pairwise cotransfection of and and and and in cells by activation in response to or as both and and and the results is inhibitory to both and and is inhibitory to These results also show that respond to both and and that human TLR7 and TLR8 that the in the response is than that of and is all the The in the inhibitory function of and inhibit and that the inhibitory function of these TLRs is evolutionarily conserved and also that the molecular interactions that are necessary for the inhibitory interactions are conserved between murine and human TLR7 and For the first results from and activation of one TLR over the other indicate that TLR7 and TLR8, TLR7 and TLR9, and TLR8 and TLR9 or through a that may and these interactions result in the of one TLR but not the other inhibits both TLR7 and TLR9, and TLR9 inhibits only Therefore, the is and is the first show that a TLR TLR8 or also play a the of other TLR Although the inhibitory effects of TLR8 on TLR7 and TLR9, and TLR9 on TLR7 in an the of these inhibitory effects in the of innate immune system response to a given PAMP is not However, are of indirect that that the inhibitory interactions among these TLRs may to the of In human immune the expression of both TLR7 and TLR9 in a given cell type is to plasmacytoid dendritic cells and cells S. S. A. T. S. G. J. Immunol. 2002; PubMed Scopus Google Scholar, Immunol. 2002; 14: PubMed Scopus Google Scholar). and agonists type I in K.B. Gorski K.S. Gibson S.J. Kedl R.M. Kieper W.C. Qiu X. Tomai M.A. Alkan S. Vasilakos J.P. J. Immunol. 2005; 174: 1259-1268Crossref PubMed Scopus (585) Google Scholar, T. 2005; PubMed Scopus Google and cell A.M. 2000; PubMed Scopus Google Scholar, C. Akira S. A. J. 2005; PubMed Scopus Google Scholar). the physical interactions between TLR7 and TLR9 are inhibitory to TLR7, and TLR7 agonists are of activation to cell or of type I in pDCs, both these cells may express an of TLR7 to the inhibitory effects of TLR9. as the inhibitory effects of TLR9 on TLR7 are more as a function of of TLR9 is that the expression of these TLRs is to the inhibitory effects of TLR9. cells express but of both TLR7 and TLR9, only in response to TLR9 agonists A. 2003; PubMed Scopus Google Scholar, T. S. G. J. Immunol. 2005; 174: PubMed Scopus Google Scholar). These to be with results that TLR9 inhibits TLR7 but not vice The that selectively TLR7 in cells in the of these cells in response to TLR7 the T. S. G. J. Immunol. 2005; 174: PubMed Scopus Google Scholar), also to that the of TLR7 is TLR9 both TLR7 and TLR9 agonists type I in pDCs, is that the of TLR9 may have for an activation of TLR7. the of both TLR8 and TLR9 in a given cell type has not been the of TLR9 by TLR8 is not In among TLR7, TLR8, and TLR9, express TLR7 and TLR9 S. S. A. T. S. G. J. Immunol. 2002; PubMed Scopus Google Scholar, Immunol. 2002; 14: PubMed Scopus Google Scholar), and myeloid express TLR8 but not TLR7 or TLR9 S.S. H. Hemmi H. Kaisho T. Reis e Akira S. Sousa C. Eur. J. Immunol. 2003; PubMed Scopus Google Scholar). However, the expression of both TLR7 and TLR8 in a given cell type is to only S. S. A. T. S. G. J. Immunol. 2002; PubMed Scopus Google and H. S. H. K. K. K. K. J. Immunol. 2003; PubMed Scopus Google Scholar). Although the express both TLR7 and TLR8, respond to only the but not to the K.B. Gorski K.S. Gibson S.J. Kedl R.M. Kieper W.C. Qiu X. Tomai M.A. Alkan S. Vasilakos J.P. J. Immunol. 2005; 174: 1259-1268Crossref PubMed Scopus (585) Google Scholar). a cell both TLR7 and TLR8 K.A. J. Immunol. 2002; PubMed Scopus Google and to only agonists in the of and Although the cells express of TLR7 with TLR8 were to any TLR7 However, cells not only express of TLR7 and TLR8 but also show of TLR7 with and to respond to the the other the cells with the of TLR8 also show a enhanced response to We were for the of TLR8 as the were of as using HEK293 cells The of any response to in cells with of to TLR7 that the TLR7 may be the inhibitory of and respond to as by up-regulation and H. S. H. K. K. K. K. J. Immunol. 2003; PubMed Scopus Google Scholar). is a both TLR7 and J. L. E. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar), is not the activation of these cells is or be of to are any inhibitory effects of TLR8 on TLR7 by the activation of these cells in response to the While is in response to any known human TLR8 agonists F. J. C. A.M. H. G. S. Nat. Immun. 2002; Scopus Google Scholar), to the agonists that or and and the necessary innate immune signals that the innate immune response of human TLR7 and The of in response to the agonists that is not to of its expression as are its expression in both immune S.S. H. Hemmi H. Kaisho T. Reis e Akira S. Sousa C. Eur. J. Immunol. 2003; PubMed Scopus Google and cells E.A. F. Finberg R.W. J. 2004; PubMed Google Scholar). In the expression of TLR7 and TLR8 in and mDCs, and their activation may immune signals that are in response to a given type of For example, activation of human TLR7 in type I as a direct and activation of human TLR8 in results in the to from among signals and is in murine and mDCs, has the to and inflammatory response to a given Therefore, in is that the inhibitory function of TLR8 may the of inflammatory response upon TLR7 activation as murine TLR8 is in all S.S. H. Hemmi H. Kaisho T. Reis e Akira S. Sousa C. Eur. J. Immunol. 2003; PubMed Scopus Google Scholar). for only from TLR8 The expression pattern of different TLRs in different immune and cells to be highly and and is different in and the expression pattern in response to different or certain These indicate that TLRs may function in with other TLRs on the type of (or and the of the The variation in of that with other in recognizing the PAMP or that to inhibit or the activation of the in response to any may play a role in the of We for expression Gibson for Tomai for of and for and on the