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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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TRIF signal pathway. In TLR1-TLR13, TRIF is the sole adaptor of TLR3 and also an adjunct adaptor of TLR4. Here, the TLR3-TRIF signal is illustrated as an example of TRIF pathway. dsRNA that is internalized in endosome binds to TLR3, which possesses two dsRNA binding sites near the N-terminus and C-terminus, respectively. When combined with dsRNA, a sole dsRNA molecule associates two TLR3 molecules through four dsRNA binding sites in an “m” shape. TLR3 TIR domain combines with the TIR domain of TRIF. The interaction of TRIF with RIP1 or TRAF6 and Peli1 results in polyubiquitination of RIP1, the latter binds ubiquitin receptors TAB2 and TAB3 which activates TAK1. Activated TAK1 induces phosphorylation of IKK complex composed of IKKα and IKKβ and NEMO. This results in the degradation of IκB which ultimately causes the nuclear translocation of NF-κB to activate the specific gene promoter A20. TAK1 also interacts with JNK and p38 to activate c-JUN and ATF2. This results in the activation of the AP-1 transcription factors family. TRIF also activates TBK1 and IKKε through NAP1 inducing phosphorylation and nuclear translocation of IRF3 culminating in IFN-β production. TRAF3 binds with the TBK1/IKKε complex inducing IRF3 activation. Combination of TRIF results in phosphorylation of Tyr759 and Tyr858 in the TLR3 TIR domain which subsequently induces the phosphorylation and degradation of IκB leading to NF-κB release. Phosphorylated Tyr759 recruits PI3K and phosphorylates kinase Akt and activates nucleic IRF3. Tyrosine kinase c-Src also plays a role in Akt activation. The unique signaling of TRIF is that it interacts with FADD through RIP1 and activates procaspase-8 to initiate cell apoptosis.
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fig6: TRIF signal pathway. In TLR1-TLR13, TRIF is the sole adaptor of TLR3 and also an adjunct adaptor of TLR4. Here, the TLR3-TRIF signal is illustrated as an example of TRIF pathway. dsRNA that is internalized in endosome binds to TLR3, which possesses two dsRNA binding sites near the N-terminus and C-terminus, respectively. When combined with dsRNA, a sole dsRNA molecule associates two TLR3 molecules through four dsRNA binding sites in an “m” shape. TLR3 TIR domain combines with the TIR domain of TRIF. The interaction of TRIF with RIP1 or TRAF6 and Peli1 results in polyubiquitination of RIP1, the latter binds ubiquitin receptors TAB2 and TAB3 which activates TAK1. Activated TAK1 induces phosphorylation of IKK complex composed of IKKα and IKKβ and NEMO. This results in the degradation of IκB which ultimately causes the nuclear translocation of NF-κB to activate the specific gene promoter A20. TAK1 also interacts with JNK and p38 to activate c-JUN and ATF2. This results in the activation of the AP-1 transcription factors family. TRIF also activates TBK1 and IKKε through NAP1 inducing phosphorylation and nuclear translocation of IRF3 culminating in IFN-β production. TRAF3 binds with the TBK1/IKKε complex inducing IRF3 activation. Combination of TRIF results in phosphorylation of Tyr759 and Tyr858 in the TLR3 TIR domain which subsequently induces the phosphorylation and degradation of IκB leading to NF-κB release. Phosphorylated Tyr759 recruits PI3K and phosphorylates kinase Akt and activates nucleic IRF3. Tyrosine kinase c-Src also plays a role in Akt activation. The unique signaling of TRIF is that it interacts with FADD through RIP1 and activates procaspase-8 to initiate cell apoptosis.

Mentions: TRIF is the sole adaptor of TLR3 and the adjunctive adaptor of TLR4. After sensing dsRNA, the TIR domain of TLR3 associates TRIF TIR, then TRIF interacts with receptor-interacting protein 1 (RIP1) through the RIP homotypic interaction motif (RHIM) present in both proteins (Figure 6). TRAF6 is also recruited to the N-terminal domain of TRIF followed by polyubiquitination of RIP1. Peli1, a member of Pellino family of RING-like domain-containing E3 ubiquitin ligases, also participates in RIP1 polyubiquitination along with TRAF6 [258]. The polyubiquitinated RIP1 recruits the ubiquitin receptor proteins TAB2 and TAB3, which in turn activate TAK1 [259]. TAK1 then phosphorylates IKKα and IKKβ leading to degradation of IκB which results in the translocation of NF-κB to cell nucleus to stimulate proinflammatory cytokine production [260]. Similar to MyD88 signaling, TAK1 activates AP1 through JNK and p38. TRIF also associates its adaptor protein NF-κB activating kinase- (NAK-) associated protein 1 (NAP1) to activate TBK1 and IKKε resulting in the phosphorylation and nuclear translocation of IRF3, inducing the expression of IFN-β [261]. TRAF3 combines with the TBK1/IKKε complex and is also involved in the TRIF-mediated IRF3 activation [245]. It is a unique signal pathway of TRIF that interacts with Fas-associated cell death domain (FADD) protein through RIP1 which in turn activates procaspase-8 to initiate cell apoptosis [262, 263]. Recently, a TIR-less splice variant of TRIF (designated as TRIS) was found capable of activating IRF3 through the interaction with TBK1 and/or activating NF-κB via RIP1 [264]. TLR3 itself is also involved in signaling, for example, the phosphorylation of Tyr759 and Tyr858 in the TLR3 TIR domain. Phosphorylated Tyr759 recruits PI3K to activate kinase Akt which in turn activates IRF3 in nucleus [265]. Additionally, the phosphorylation of Tyr759 and Tyr858 induces degradation of IκB to release and partially activate NF-κB by phosphorylation [266]. Tyrosine kinase c-Src also involves Akt activation [267].


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)

TRIF signal pathway. In TLR1-TLR13, TRIF is the sole adaptor of TLR3 and also an adjunct adaptor of TLR4. Here, the TLR3-TRIF signal is illustrated as an example of TRIF pathway. dsRNA that is internalized in endosome binds to TLR3, which possesses two dsRNA binding sites near the N-terminus and C-terminus, respectively. When combined with dsRNA, a sole dsRNA molecule associates two TLR3 molecules through four dsRNA binding sites in an “m” shape. TLR3 TIR domain combines with the TIR domain of TRIF. The interaction of TRIF with RIP1 or TRAF6 and Peli1 results in polyubiquitination of RIP1, the latter binds ubiquitin receptors TAB2 and TAB3 which activates TAK1. Activated TAK1 induces phosphorylation of IKK complex composed of IKKα and IKKβ and NEMO. This results in the degradation of IκB which ultimately causes the nuclear translocation of NF-κB to activate the specific gene promoter A20. TAK1 also interacts with JNK and p38 to activate c-JUN and ATF2. This results in the activation of the AP-1 transcription factors family. TRIF also activates TBK1 and IKKε through NAP1 inducing phosphorylation and nuclear translocation of IRF3 culminating in IFN-β production. TRAF3 binds with the TBK1/IKKε complex inducing IRF3 activation. Combination of TRIF results in phosphorylation of Tyr759 and Tyr858 in the TLR3 TIR domain which subsequently induces the phosphorylation and degradation of IκB leading to NF-κB release. Phosphorylated Tyr759 recruits PI3K and phosphorylates kinase Akt and activates nucleic IRF3. Tyrosine kinase c-Src also plays a role in Akt activation. The unique signaling of TRIF is that it interacts with FADD through RIP1 and activates procaspase-8 to initiate cell apoptosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig6: TRIF signal pathway. In TLR1-TLR13, TRIF is the sole adaptor of TLR3 and also an adjunct adaptor of TLR4. Here, the TLR3-TRIF signal is illustrated as an example of TRIF pathway. dsRNA that is internalized in endosome binds to TLR3, which possesses two dsRNA binding sites near the N-terminus and C-terminus, respectively. When combined with dsRNA, a sole dsRNA molecule associates two TLR3 molecules through four dsRNA binding sites in an “m” shape. TLR3 TIR domain combines with the TIR domain of TRIF. The interaction of TRIF with RIP1 or TRAF6 and Peli1 results in polyubiquitination of RIP1, the latter binds ubiquitin receptors TAB2 and TAB3 which activates TAK1. Activated TAK1 induces phosphorylation of IKK complex composed of IKKα and IKKβ and NEMO. This results in the degradation of IκB which ultimately causes the nuclear translocation of NF-κB to activate the specific gene promoter A20. TAK1 also interacts with JNK and p38 to activate c-JUN and ATF2. This results in the activation of the AP-1 transcription factors family. TRIF also activates TBK1 and IKKε through NAP1 inducing phosphorylation and nuclear translocation of IRF3 culminating in IFN-β production. TRAF3 binds with the TBK1/IKKε complex inducing IRF3 activation. Combination of TRIF results in phosphorylation of Tyr759 and Tyr858 in the TLR3 TIR domain which subsequently induces the phosphorylation and degradation of IκB leading to NF-κB release. Phosphorylated Tyr759 recruits PI3K and phosphorylates kinase Akt and activates nucleic IRF3. Tyrosine kinase c-Src also plays a role in Akt activation. The unique signaling of TRIF is that it interacts with FADD through RIP1 and activates procaspase-8 to initiate cell apoptosis.
Mentions: TRIF is the sole adaptor of TLR3 and the adjunctive adaptor of TLR4. After sensing dsRNA, the TIR domain of TLR3 associates TRIF TIR, then TRIF interacts with receptor-interacting protein 1 (RIP1) through the RIP homotypic interaction motif (RHIM) present in both proteins (Figure 6). TRAF6 is also recruited to the N-terminal domain of TRIF followed by polyubiquitination of RIP1. Peli1, a member of Pellino family of RING-like domain-containing E3 ubiquitin ligases, also participates in RIP1 polyubiquitination along with TRAF6 [258]. The polyubiquitinated RIP1 recruits the ubiquitin receptor proteins TAB2 and TAB3, which in turn activate TAK1 [259]. TAK1 then phosphorylates IKKα and IKKβ leading to degradation of IκB which results in the translocation of NF-κB to cell nucleus to stimulate proinflammatory cytokine production [260]. Similar to MyD88 signaling, TAK1 activates AP1 through JNK and p38. TRIF also associates its adaptor protein NF-κB activating kinase- (NAK-) associated protein 1 (NAP1) to activate TBK1 and IKKε resulting in the phosphorylation and nuclear translocation of IRF3, inducing the expression of IFN-β [261]. TRAF3 combines with the TBK1/IKKε complex and is also involved in the TRIF-mediated IRF3 activation [245]. It is a unique signal pathway of TRIF that interacts with Fas-associated cell death domain (FADD) protein through RIP1 which in turn activates procaspase-8 to initiate cell apoptosis [262, 263]. Recently, a TIR-less splice variant of TRIF (designated as TRIS) was found capable of activating IRF3 through the interaction with TBK1 and/or activating NF-κB via RIP1 [264]. TLR3 itself is also involved in signaling, for example, the phosphorylation of Tyr759 and Tyr858 in the TLR3 TIR domain. Phosphorylated Tyr759 recruits PI3K to activate kinase Akt which in turn activates IRF3 in nucleus [265]. Additionally, the phosphorylation of Tyr759 and Tyr858 induces degradation of IκB to release and partially activate NF-κB by phosphorylation [266]. Tyrosine kinase c-Src also involves Akt activation [267].

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