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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.

Show MeSH
Peripheral T-cell tolerance in lymph node. All the subsets of LNSC can express PTA. AIRE and Deaf1 are involved in the regulation of this expression. Both the LNSC and follicular DC in lymph node can serve as APC to present or cross-present self-epitopes to T cells. Lymph contains abundant-processed protein fragments and peptides from draining organs or tissues and serves as a significant pool of self-antigen for the induction of peripheral tolerance. LNSC can upregulate co-stimulatory molecules to induce T-cell lineage deletion. The autoreactive T-cell lineage deletion is mediated by apoptosis mediated by Fas or Bim signals when inflammation is absent. The engagement of Fas ligand with Fas on T-cell surface triggers the apoptosis of activated T cell through caspase-dependent pathway. T-cell stimulation causes downregulation of Bcl-2 and a transient slight upregulation of Bim and this results in increased uncomplex Bim which is combined with Bcl-2 in resting status. This then activates Bcl-2 homologous antagonist/killer (Bak) and Bcl-2–associated X protein (Bax). Consequently, the integrity of mitochondria is damaged and this culminates in cell death. The tolerogenic DCs induce T-cell functional tolerance, that is, anergy by upregulation of either CTLA-4 or PD-1 expression in T cells. Augmented expression of CTLA-4 can block co-stimulatory signals by binding to CD80/86 in competition with CD28 to induce T-cell anergy. In recognition of self-antigen, PD-L1 on tolerogenic DCs interacts with PD-1 on T cells to limit T-cell activity in peripheral tissues and maintain T cell in unresponsiveness. PD-1 suppresses the PI3K induction and Akt activation. This disturbs cellular glucose metabolism and impairs T-cell survival. PD-1 activation also inhibits the cell-survival factor Bcl-xL production. CTLA-4 engagement blocks Akt phosphorylation by activation of protein phosphatase 2. Engagement of both PD-1 and CTLA-4 can significantly decrease gene transcriptions of T cell being activated.
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fig3: Peripheral T-cell tolerance in lymph node. All the subsets of LNSC can express PTA. AIRE and Deaf1 are involved in the regulation of this expression. Both the LNSC and follicular DC in lymph node can serve as APC to present or cross-present self-epitopes to T cells. Lymph contains abundant-processed protein fragments and peptides from draining organs or tissues and serves as a significant pool of self-antigen for the induction of peripheral tolerance. LNSC can upregulate co-stimulatory molecules to induce T-cell lineage deletion. The autoreactive T-cell lineage deletion is mediated by apoptosis mediated by Fas or Bim signals when inflammation is absent. The engagement of Fas ligand with Fas on T-cell surface triggers the apoptosis of activated T cell through caspase-dependent pathway. T-cell stimulation causes downregulation of Bcl-2 and a transient slight upregulation of Bim and this results in increased uncomplex Bim which is combined with Bcl-2 in resting status. This then activates Bcl-2 homologous antagonist/killer (Bak) and Bcl-2–associated X protein (Bax). Consequently, the integrity of mitochondria is damaged and this culminates in cell death. The tolerogenic DCs induce T-cell functional tolerance, that is, anergy by upregulation of either CTLA-4 or PD-1 expression in T cells. Augmented expression of CTLA-4 can block co-stimulatory signals by binding to CD80/86 in competition with CD28 to induce T-cell anergy. In recognition of self-antigen, PD-L1 on tolerogenic DCs interacts with PD-1 on T cells to limit T-cell activity in peripheral tissues and maintain T cell in unresponsiveness. PD-1 suppresses the PI3K induction and Akt activation. This disturbs cellular glucose metabolism and impairs T-cell survival. PD-1 activation also inhibits the cell-survival factor Bcl-xL production. CTLA-4 engagement blocks Akt phosphorylation by activation of protein phosphatase 2. Engagement of both PD-1 and CTLA-4 can significantly decrease gene transcriptions of T cell being activated.

Mentions: Self-tolerance is induced in thymus either by negative selection or by natural regulatory T cells (nTreg) development. Most of the nTreg cells are derived from CD4+ SP thymocytes residing in the medullary compartment of the thymus [40, 41]. It is hypothesized that tolerance of uncommon self-antigens such as myosin usually presents after muscle injury is preferentially recognized by TCR and mediated by nTreg cells. By contrast, cells that are involved in chronic engagement of TCR/CD28 signaling by recognizing ubiquitous antigen, for example, albumin, the 5th component of complement, insulin, are negatively selected [40, 42, 43]. Decreased presentation of cognate antigens on mTECs or DCs can induce nTreg cell development [44]. Distinct APC subsets may preserve different TCR specificities and their ability to mediate negative selection [40, 45–47]. It has been suggested that forkhead box P3 (Foxp3) negative nTreg cell precursors, induced by TCR signaling, can use interleukin-2 (IL-2), IL-15, or IL-7 to activate Foxp3 expression without the need for additional TCR signals [40]. It is believed that nTreg cell development begins early at the DP stage in pediatric thymus. Foxp3+ DP thymocytes with a functional IL-7 receptor and upregulated expression of Bcl-2 protect themselves from being negative selected. Foxp3+ DP thymocytes that express CD103 are possible precursor of Foxp3+ CD8+ SP cells [48]. Hassall's corpuscles, groups of epithelial cells in the thymic medulla, may serve as specialized small niches required to support nascent nTreg cell development [49].


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)

Peripheral T-cell tolerance in lymph node. All the subsets of LNSC can express PTA. AIRE and Deaf1 are involved in the regulation of this expression. Both the LNSC and follicular DC in lymph node can serve as APC to present or cross-present self-epitopes to T cells. Lymph contains abundant-processed protein fragments and peptides from draining organs or tissues and serves as a significant pool of self-antigen for the induction of peripheral tolerance. LNSC can upregulate co-stimulatory molecules to induce T-cell lineage deletion. The autoreactive T-cell lineage deletion is mediated by apoptosis mediated by Fas or Bim signals when inflammation is absent. The engagement of Fas ligand with Fas on T-cell surface triggers the apoptosis of activated T cell through caspase-dependent pathway. T-cell stimulation causes downregulation of Bcl-2 and a transient slight upregulation of Bim and this results in increased uncomplex Bim which is combined with Bcl-2 in resting status. This then activates Bcl-2 homologous antagonist/killer (Bak) and Bcl-2–associated X protein (Bax). Consequently, the integrity of mitochondria is damaged and this culminates in cell death. The tolerogenic DCs induce T-cell functional tolerance, that is, anergy by upregulation of either CTLA-4 or PD-1 expression in T cells. Augmented expression of CTLA-4 can block co-stimulatory signals by binding to CD80/86 in competition with CD28 to induce T-cell anergy. In recognition of self-antigen, PD-L1 on tolerogenic DCs interacts with PD-1 on T cells to limit T-cell activity in peripheral tissues and maintain T cell in unresponsiveness. PD-1 suppresses the PI3K induction and Akt activation. This disturbs cellular glucose metabolism and impairs T-cell survival. PD-1 activation also inhibits the cell-survival factor Bcl-xL production. CTLA-4 engagement blocks Akt phosphorylation by activation of protein phosphatase 2. Engagement of both PD-1 and CTLA-4 can significantly decrease gene transcriptions of T cell being activated.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig3: Peripheral T-cell tolerance in lymph node. All the subsets of LNSC can express PTA. AIRE and Deaf1 are involved in the regulation of this expression. Both the LNSC and follicular DC in lymph node can serve as APC to present or cross-present self-epitopes to T cells. Lymph contains abundant-processed protein fragments and peptides from draining organs or tissues and serves as a significant pool of self-antigen for the induction of peripheral tolerance. LNSC can upregulate co-stimulatory molecules to induce T-cell lineage deletion. The autoreactive T-cell lineage deletion is mediated by apoptosis mediated by Fas or Bim signals when inflammation is absent. The engagement of Fas ligand with Fas on T-cell surface triggers the apoptosis of activated T cell through caspase-dependent pathway. T-cell stimulation causes downregulation of Bcl-2 and a transient slight upregulation of Bim and this results in increased uncomplex Bim which is combined with Bcl-2 in resting status. This then activates Bcl-2 homologous antagonist/killer (Bak) and Bcl-2–associated X protein (Bax). Consequently, the integrity of mitochondria is damaged and this culminates in cell death. The tolerogenic DCs induce T-cell functional tolerance, that is, anergy by upregulation of either CTLA-4 or PD-1 expression in T cells. Augmented expression of CTLA-4 can block co-stimulatory signals by binding to CD80/86 in competition with CD28 to induce T-cell anergy. In recognition of self-antigen, PD-L1 on tolerogenic DCs interacts with PD-1 on T cells to limit T-cell activity in peripheral tissues and maintain T cell in unresponsiveness. PD-1 suppresses the PI3K induction and Akt activation. This disturbs cellular glucose metabolism and impairs T-cell survival. PD-1 activation also inhibits the cell-survival factor Bcl-xL production. CTLA-4 engagement blocks Akt phosphorylation by activation of protein phosphatase 2. Engagement of both PD-1 and CTLA-4 can significantly decrease gene transcriptions of T cell being activated.
Mentions: Self-tolerance is induced in thymus either by negative selection or by natural regulatory T cells (nTreg) development. Most of the nTreg cells are derived from CD4+ SP thymocytes residing in the medullary compartment of the thymus [40, 41]. It is hypothesized that tolerance of uncommon self-antigens such as myosin usually presents after muscle injury is preferentially recognized by TCR and mediated by nTreg cells. By contrast, cells that are involved in chronic engagement of TCR/CD28 signaling by recognizing ubiquitous antigen, for example, albumin, the 5th component of complement, insulin, are negatively selected [40, 42, 43]. Decreased presentation of cognate antigens on mTECs or DCs can induce nTreg cell development [44]. Distinct APC subsets may preserve different TCR specificities and their ability to mediate negative selection [40, 45–47]. It has been suggested that forkhead box P3 (Foxp3) negative nTreg cell precursors, induced by TCR signaling, can use interleukin-2 (IL-2), IL-15, or IL-7 to activate Foxp3 expression without the need for additional TCR signals [40]. It is believed that nTreg cell development begins early at the DP stage in pediatric thymus. Foxp3+ DP thymocytes with a functional IL-7 receptor and upregulated expression of Bcl-2 protect themselves from being negative selected. Foxp3+ DP thymocytes that express CD103 are possible precursor of Foxp3+ CD8+ SP cells [48]. Hassall's corpuscles, groups of epithelial cells in the thymic medulla, may serve as specialized small niches required to support nascent nTreg cell development [49].

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