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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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Costimulation of T cells. Antigen uptake by DCs is followed by epitope presentation by MHC complex molecules to TCR expressed on T-cells surface (signal 1). Upon TCR-activation signal, T cells produce CD154 to bind CD40 on the cell surfaces of DCs to further activate DCs. After interacting with TLRs, DCs express CD80 and CD86 which combine with CD28 in T cells for costimulation of T cells (signal 2). Activated DCs also produce cytokines to instruct T cells for polarized differentiation (signal 3). TLRs expressed in T cells act as co-stimulatory molecules in T-cell activation by reducing the activation requirements for signals 1 and 2 and generating efficient memory T cell in response to a weak signal 1. Some TLR ligands even can induce signal 2 in the absence of CD28 via activation of TLR expressed on T cells.
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fig7: Costimulation of T cells. Antigen uptake by DCs is followed by epitope presentation by MHC complex molecules to TCR expressed on T-cells surface (signal 1). Upon TCR-activation signal, T cells produce CD154 to bind CD40 on the cell surfaces of DCs to further activate DCs. After interacting with TLRs, DCs express CD80 and CD86 which combine with CD28 in T cells for costimulation of T cells (signal 2). Activated DCs also produce cytokines to instruct T cells for polarized differentiation (signal 3). TLRs expressed in T cells act as co-stimulatory molecules in T-cell activation by reducing the activation requirements for signals 1 and 2 and generating efficient memory T cell in response to a weak signal 1. Some TLR ligands even can induce signal 2 in the absence of CD28 via activation of TLR expressed on T cells.

Mentions: TLRs expressed in T cells have been suggested to act as co-stimulatory molecules involved in T-cell activation [268, 277]. Application of Pam3CysSK4, the ligand of TLR1/TLR2 complex, in activated TCR transgenic mice CD8+ T cells resulted in increased cell proliferation and survival. This was associated with a sustained CD25 expression and an enhanced expression of Bcl-xL, an antiapoptotic molecule. TLR2 engagement also enhances production of IFN-γ and granzyme B, promotes cytotoxic activity of antigen-activated CD8+ T cells, reduces the activation requirements for co-stimulatory signals from APC and TCR signal strength, and generates efficient memory T cells in response to a weak TCR signal [308, 309]. TLR2 engagement on CD8+ memory T cells is also involved in the direct control of memory cell proliferation and IFN-γ production [310]. The co-stimulatory role of TLR2 ligation on CD8+ T cell is believed to be due to the intrinsic TLR2-MyD88 signaling and PI3K-Akt pathway activation in CD8+ T cells [308, 311]. PI3K signal activated by MyD88 adaptor is indispensable to the costimulation of CD4+ T cells by TLR9 ligand CpG ODN [312]. Costimulation by poly(I:C) of naive CD4+ T cells through TLR3 in the presence of anti-CD3 and anti-CD28 can induce synthesis of IL-17A and IL-21, this being dependent on activation of the NF-κB pathway. IL-17A and IL-21 cause naive CD4+ T-cell differentiation toward an IL-21 phenotype. These cells do not have the transcription factors T-bet, GATA-3 and ROR-c that represent the induction of Th1, Th2 and Th17 subsets, respectively [313] and consequently such cells are absent. TLR ligands can act directly on highly purified T cells in the absence of CD28 engagement [303] but is unable to induce functional responses in naive T cells without concurrent TCR stimulation [308]. Therefore, TLR-induced signals in T cells are strictly co-stimulatory [303] (Figure 7).


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)

Costimulation of T cells. Antigen uptake by DCs is followed by epitope presentation by MHC complex molecules to TCR expressed on T-cells surface (signal 1). Upon TCR-activation signal, T cells produce CD154 to bind CD40 on the cell surfaces of DCs to further activate DCs. After interacting with TLRs, DCs express CD80 and CD86 which combine with CD28 in T cells for costimulation of T cells (signal 2). Activated DCs also produce cytokines to instruct T cells for polarized differentiation (signal 3). TLRs expressed in T cells act as co-stimulatory molecules in T-cell activation by reducing the activation requirements for signals 1 and 2 and generating efficient memory T cell in response to a weak signal 1. Some TLR ligands even can induce signal 2 in the absence of CD28 via activation of TLR expressed on T cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig7: Costimulation of T cells. Antigen uptake by DCs is followed by epitope presentation by MHC complex molecules to TCR expressed on T-cells surface (signal 1). Upon TCR-activation signal, T cells produce CD154 to bind CD40 on the cell surfaces of DCs to further activate DCs. After interacting with TLRs, DCs express CD80 and CD86 which combine with CD28 in T cells for costimulation of T cells (signal 2). Activated DCs also produce cytokines to instruct T cells for polarized differentiation (signal 3). TLRs expressed in T cells act as co-stimulatory molecules in T-cell activation by reducing the activation requirements for signals 1 and 2 and generating efficient memory T cell in response to a weak signal 1. Some TLR ligands even can induce signal 2 in the absence of CD28 via activation of TLR expressed on T cells.
Mentions: TLRs expressed in T cells have been suggested to act as co-stimulatory molecules involved in T-cell activation [268, 277]. Application of Pam3CysSK4, the ligand of TLR1/TLR2 complex, in activated TCR transgenic mice CD8+ T cells resulted in increased cell proliferation and survival. This was associated with a sustained CD25 expression and an enhanced expression of Bcl-xL, an antiapoptotic molecule. TLR2 engagement also enhances production of IFN-γ and granzyme B, promotes cytotoxic activity of antigen-activated CD8+ T cells, reduces the activation requirements for co-stimulatory signals from APC and TCR signal strength, and generates efficient memory T cells in response to a weak TCR signal [308, 309]. TLR2 engagement on CD8+ memory T cells is also involved in the direct control of memory cell proliferation and IFN-γ production [310]. The co-stimulatory role of TLR2 ligation on CD8+ T cell is believed to be due to the intrinsic TLR2-MyD88 signaling and PI3K-Akt pathway activation in CD8+ T cells [308, 311]. PI3K signal activated by MyD88 adaptor is indispensable to the costimulation of CD4+ T cells by TLR9 ligand CpG ODN [312]. Costimulation by poly(I:C) of naive CD4+ T cells through TLR3 in the presence of anti-CD3 and anti-CD28 can induce synthesis of IL-17A and IL-21, this being dependent on activation of the NF-κB pathway. IL-17A and IL-21 cause naive CD4+ T-cell differentiation toward an IL-21 phenotype. These cells do not have the transcription factors T-bet, GATA-3 and ROR-c that represent the induction of Th1, Th2 and Th17 subsets, respectively [313] and consequently such cells are absent. TLR ligands can act directly on highly purified T cells in the absence of CD28 engagement [303] but is unable to induce functional responses in naive T cells without concurrent TCR stimulation [308]. Therefore, TLR-induced signals in T cells are strictly co-stimulatory [303] (Figure 7).

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