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The effects of TLR activation on T-cell development and differentiation.

Jin B, Sun T, Yu XH, Yang YX, Yeo AE - Clin. Dev. Immunol. (2012)

Bottom Line: Invading pathogens have unique molecular signatures that are recognized by Toll-like receptors (TLRs) resulting in either activation of antigen-presenting cells (APCs) and/or costimulation of T cells inducing both innate and adaptive immunity.T-cell receptor (TCR) activation in distinct T-cell subsets with different TLRs results in differing outcomes, for example, activation of TLR4 expressed in T cells promotes suppressive function of regulatory T cells (Treg), while activation of TLR6 expressed in T cells abrogates Treg function.The current state of knowledge of regarding TLR-mediated T-cell development and differentiation is reviewed.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, The 309th Hospital of The People's Liberation Army, Beijing, China. bjbo.jin@gmail.com

ABSTRACT
Invading pathogens have unique molecular signatures that are recognized by Toll-like receptors (TLRs) resulting in either activation of antigen-presenting cells (APCs) and/or costimulation of T cells inducing both innate and adaptive immunity. TLRs are also involved in T-cell development and can reprogram Treg cells to become helper cells. T cells consist of various subsets, that is, Th1, Th2, Th17, T follicular helper (Tfh), cytotoxic T lymphocytes (CTLs), regulatory T cells (Treg) and these originate from thymic progenitor thymocytes. T-cell receptor (TCR) activation in distinct T-cell subsets with different TLRs results in differing outcomes, for example, activation of TLR4 expressed in T cells promotes suppressive function of regulatory T cells (Treg), while activation of TLR6 expressed in T cells abrogates Treg function. The current state of knowledge of regarding TLR-mediated T-cell development and differentiation is reviewed.

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MyD88 signal pathway. MyD88 is the universal adaptor of all the identified TLRs except TLR3. In this figure, TLR1/TLR2 is used to illustrate the MyD88 signal pathway. TLR1/TLR2 uses triacryl lipopeptide as the ligand to recruit MyD88 via its cytoplasmic TIR domain. MyD88 interacts with DD to associate with IRAK4. IRAK4 then phosphorates IRAK1 and IRAK2 activates TRAF6. TRAF6 induces the synthesis of polyubiquitin chains that links TRAF6, NEMO, IRAK1 and TAB2, 3, 4. The ubiquitination of TAB2/3/4 in association with TAB1 activates TAK1. This induces phosphorylation of IKK complex resulting in the dissociation of IκB and NF-κB. NF-κB then translocates into nucleus to induce the gene transcription of proinflammatory cytokines. TAK1 also activates JNK and p38 which induce AP1 activation. MyD88 and TRAF6 both activate IRF5 and induce proinflammatory cytokines. This activation is inhibited by IRF4. TRAF6 also interacts with TRAF3 and then recruits TBK1 to activate IRF3 and IFN-β production. TRAF3 alternatively induces the anti-inflammatory cytokine IL-10.
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fig5: MyD88 signal pathway. MyD88 is the universal adaptor of all the identified TLRs except TLR3. In this figure, TLR1/TLR2 is used to illustrate the MyD88 signal pathway. TLR1/TLR2 uses triacryl lipopeptide as the ligand to recruit MyD88 via its cytoplasmic TIR domain. MyD88 interacts with DD to associate with IRAK4. IRAK4 then phosphorates IRAK1 and IRAK2 activates TRAF6. TRAF6 induces the synthesis of polyubiquitin chains that links TRAF6, NEMO, IRAK1 and TAB2, 3, 4. The ubiquitination of TAB2/3/4 in association with TAB1 activates TAK1. This induces phosphorylation of IKK complex resulting in the dissociation of IκB and NF-κB. NF-κB then translocates into nucleus to induce the gene transcription of proinflammatory cytokines. TAK1 also activates JNK and p38 which induce AP1 activation. MyD88 and TRAF6 both activate IRF5 and induce proinflammatory cytokines. This activation is inhibited by IRF4. TRAF6 also interacts with TRAF3 and then recruits TBK1 to activate IRF3 and IFN-β production. TRAF3 alternatively induces the anti-inflammatory cytokine IL-10.

Mentions: MyD88 is the essential adaptor for most TLRs. Upon ligand recognition, TLR recruits MyD88 to its cytoplasmic TIR domain by association with the TIR domain of the adaptor molecule (Figure 5). MyD88 possesses an N-terminal death domain (DD) that associates with DD of IL-1R-associated kinase-4 (IRAK4) [235]. IRAK1 and IRAK2 are phosphorylated by IRAK4 and then activate TNF receptor associated factor-6 (TRAF6) [236, 237]. TRAF6 acts as an E3 ubiquitin protein ligase to ubiquitinate itself and NF-κB essential modulator (NEMO) by the formation of polyubiquitin chains. Both TRAF6 and NEMO are connected with IRAK1 by the chains. These chains also connect NEMO with the transforming growth factor β-activated kinase-1- (TAK1-) binding proteins (TABs) including TAB2, 3 and 4 which promote phosphorylation of TAK1-TAB1 resulting in TAK1 activation [238–241]. The activated TAK1 induces phosphorylation of IκB kinase-related kinase (IKK) β. This causes IκB phosphorylation and its dissociation with NF-κB. Consequently, the nuclear translocation of NF-κB is induced and this culminates in the transcription of proinflammatory cytokines, for example, TNF and IL-6. The TAK1/TABs complex also phosphorylates and activates c-Jun N-terminal kinase (JNK) and p38 resulting in activation of activator protein 1 (AP1) [216, 227]. IRF5 can be activated by both MyD88 and TRAF6, and it promotes the transcription of proinflammatory cytokines [242]. This can be inhibited by the competition by IRF4 [243]. TRAF6 also induces TRAF3 triggering noncanonical TRAF3 self-ubiquitination [244] and this complex associates with TRAF family-member-associated NF-κB activator-binding kinase 1 (TBK1). It then acts with IRF3 to induce IFN-β production. Ubiquitinated TRAF3 also induces the anti-inflammatory cytokine IL-10 [245, 246]. In plasmacytoid DCs (pDCs), MyD88 signaling elicited by TLR7 and TLR9 is different from that in myeloid DCs (mDCs). Through phosphatidylinositol 3-kinase (PI3K), MyD88 signaling in pDCs ultimately activates IRF7 to induce production of enormous quantities of IFN-α [247–249]. In humans, TLR3 is predominantly expressed in mDCs whereas TLR7 and TLR9 are exclusively expressed in pDCs [250–255]. TLR expressions in murine DCs are not restricted as seen in human DCs. In mice, mDCs (alternatively named conventional DCs, cDCs) express all TLRs except TLR7 which is not expressed by CD8α+ mDCs [250, 256]. Indeed, murine pDCs highly express TLR7 and TLR9 along with mRNAs of all the remaining identified TLRs. TLR3 is preferentially expressed in CD8α+ mDCs and possibly not expressed in pDCs [250, 256]. Therefore, effective antitumor immunity elicited by CpG DNA in mouse is not seen in humans [257].


The effects of TLR activation on T-cell development and differentiation.

Jin B, Sun T, Yu XH, Yang YX, Yeo AE - Clin. Dev. Immunol. (2012)

MyD88 signal pathway. MyD88 is the universal adaptor of all the identified TLRs except TLR3. In this figure, TLR1/TLR2 is used to illustrate the MyD88 signal pathway. TLR1/TLR2 uses triacryl lipopeptide as the ligand to recruit MyD88 via its cytoplasmic TIR domain. MyD88 interacts with DD to associate with IRAK4. IRAK4 then phosphorates IRAK1 and IRAK2 activates TRAF6. TRAF6 induces the synthesis of polyubiquitin chains that links TRAF6, NEMO, IRAK1 and TAB2, 3, 4. The ubiquitination of TAB2/3/4 in association with TAB1 activates TAK1. This induces phosphorylation of IKK complex resulting in the dissociation of IκB and NF-κB. NF-κB then translocates into nucleus to induce the gene transcription of proinflammatory cytokines. TAK1 also activates JNK and p38 which induce AP1 activation. MyD88 and TRAF6 both activate IRF5 and induce proinflammatory cytokines. This activation is inhibited by IRF4. TRAF6 also interacts with TRAF3 and then recruits TBK1 to activate IRF3 and IFN-β production. TRAF3 alternatively induces the anti-inflammatory cytokine IL-10.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig5: MyD88 signal pathway. MyD88 is the universal adaptor of all the identified TLRs except TLR3. In this figure, TLR1/TLR2 is used to illustrate the MyD88 signal pathway. TLR1/TLR2 uses triacryl lipopeptide as the ligand to recruit MyD88 via its cytoplasmic TIR domain. MyD88 interacts with DD to associate with IRAK4. IRAK4 then phosphorates IRAK1 and IRAK2 activates TRAF6. TRAF6 induces the synthesis of polyubiquitin chains that links TRAF6, NEMO, IRAK1 and TAB2, 3, 4. The ubiquitination of TAB2/3/4 in association with TAB1 activates TAK1. This induces phosphorylation of IKK complex resulting in the dissociation of IκB and NF-κB. NF-κB then translocates into nucleus to induce the gene transcription of proinflammatory cytokines. TAK1 also activates JNK and p38 which induce AP1 activation. MyD88 and TRAF6 both activate IRF5 and induce proinflammatory cytokines. This activation is inhibited by IRF4. TRAF6 also interacts with TRAF3 and then recruits TBK1 to activate IRF3 and IFN-β production. TRAF3 alternatively induces the anti-inflammatory cytokine IL-10.
Mentions: MyD88 is the essential adaptor for most TLRs. Upon ligand recognition, TLR recruits MyD88 to its cytoplasmic TIR domain by association with the TIR domain of the adaptor molecule (Figure 5). MyD88 possesses an N-terminal death domain (DD) that associates with DD of IL-1R-associated kinase-4 (IRAK4) [235]. IRAK1 and IRAK2 are phosphorylated by IRAK4 and then activate TNF receptor associated factor-6 (TRAF6) [236, 237]. TRAF6 acts as an E3 ubiquitin protein ligase to ubiquitinate itself and NF-κB essential modulator (NEMO) by the formation of polyubiquitin chains. Both TRAF6 and NEMO are connected with IRAK1 by the chains. These chains also connect NEMO with the transforming growth factor β-activated kinase-1- (TAK1-) binding proteins (TABs) including TAB2, 3 and 4 which promote phosphorylation of TAK1-TAB1 resulting in TAK1 activation [238–241]. The activated TAK1 induces phosphorylation of IκB kinase-related kinase (IKK) β. This causes IκB phosphorylation and its dissociation with NF-κB. Consequently, the nuclear translocation of NF-κB is induced and this culminates in the transcription of proinflammatory cytokines, for example, TNF and IL-6. The TAK1/TABs complex also phosphorylates and activates c-Jun N-terminal kinase (JNK) and p38 resulting in activation of activator protein 1 (AP1) [216, 227]. IRF5 can be activated by both MyD88 and TRAF6, and it promotes the transcription of proinflammatory cytokines [242]. This can be inhibited by the competition by IRF4 [243]. TRAF6 also induces TRAF3 triggering noncanonical TRAF3 self-ubiquitination [244] and this complex associates with TRAF family-member-associated NF-κB activator-binding kinase 1 (TBK1). It then acts with IRF3 to induce IFN-β production. Ubiquitinated TRAF3 also induces the anti-inflammatory cytokine IL-10 [245, 246]. In plasmacytoid DCs (pDCs), MyD88 signaling elicited by TLR7 and TLR9 is different from that in myeloid DCs (mDCs). Through phosphatidylinositol 3-kinase (PI3K), MyD88 signaling in pDCs ultimately activates IRF7 to induce production of enormous quantities of IFN-α [247–249]. In humans, TLR3 is predominantly expressed in mDCs whereas TLR7 and TLR9 are exclusively expressed in pDCs [250–255]. TLR expressions in murine DCs are not restricted as seen in human DCs. In mice, mDCs (alternatively named conventional DCs, cDCs) express all TLRs except TLR7 which is not expressed by CD8α+ mDCs [250, 256]. Indeed, murine pDCs highly express TLR7 and TLR9 along with mRNAs of all the remaining identified TLRs. TLR3 is preferentially expressed in CD8α+ mDCs and possibly not expressed in pDCs [250, 256]. Therefore, effective antitumor immunity elicited by CpG DNA in mouse is not seen in humans [257].

Bottom Line: Invading pathogens have unique molecular signatures that are recognized by Toll-like receptors (TLRs) resulting in either activation of antigen-presenting cells (APCs) and/or costimulation of T cells inducing both innate and adaptive immunity.T-cell receptor (TCR) activation in distinct T-cell subsets with different TLRs results in differing outcomes, for example, activation of TLR4 expressed in T cells promotes suppressive function of regulatory T cells (Treg), while activation of TLR6 expressed in T cells abrogates Treg function.The current state of knowledge of regarding TLR-mediated T-cell development and differentiation is reviewed.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, The 309th Hospital of The People's Liberation Army, Beijing, China. bjbo.jin@gmail.com

ABSTRACT
Invading pathogens have unique molecular signatures that are recognized by Toll-like receptors (TLRs) resulting in either activation of antigen-presenting cells (APCs) and/or costimulation of T cells inducing both innate and adaptive immunity. TLRs are also involved in T-cell development and can reprogram Treg cells to become helper cells. T cells consist of various subsets, that is, Th1, Th2, Th17, T follicular helper (Tfh), cytotoxic T lymphocytes (CTLs), regulatory T cells (Treg) and these originate from thymic progenitor thymocytes. T-cell receptor (TCR) activation in distinct T-cell subsets with different TLRs results in differing outcomes, for example, activation of TLR4 expressed in T cells promotes suppressive function of regulatory T cells (Treg), while activation of TLR6 expressed in T cells abrogates Treg function. The current state of knowledge of regarding TLR-mediated T-cell development and differentiation is reviewed.

Show MeSH
Related in: MedlinePlus