Molecular mechanisms of T-cell anergy

Куклина, Е. М.

doi:10.1134/s000629791302003x

Cited by 19 publications

(18 citation statements)

References 155 publications

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“…Other signals required for T cell activation include costimulatory molecules, e.g., CD80 and CD86 (23–25). T cells that receive signals only via TCR by engagement with MHC-peptide complex, without receiving the second signal from costimulatory ligands, are destined to undergo anergy (26). Moreover, the local cytokine niche determines the type of T cell response generated.…”

Section: Discussionmentioning

confidence: 99%

Differential Cultivation of Francisella tularensis Induces Changes in the Immune Response to and Protective Efficacy of Whole Cell-Based Inactivated Vaccines

et al. 2017

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Francisella tularensis (Ft) is a category A biothreat agent for which there is no Food and Drug Administration-approved vaccine. Ft can survive in a variety of habitats with a remarkable ability to adapt to changing environmental conditions. Furthermore, Ft expresses distinct sets of antigens (Ags) when inside of macrophages (its in vivo host) as compared to those grown in vitro with Mueller Hinton Broth (MHB). However, in contrast to MHB-grown Ft, Ft grown in Brain-Heart Infusion (BHI) more closely mimics the antigenic profile of macrophage-grown Ft. Thus, we anticipated that when used as a vaccine, BHI-grown Ft would provide better protection compared to MHB-grown Ft, primarily due to its greater antigenic similarity to Ft circulating inside the host (macrophages) during natural infection. Our investigation, however, revealed that inactivated Ft (iFt) grown in MHB (iFt-MHB) exhibited superior protective activity when used as a vaccine, as compared to iFt grown in BHI (iFt-BHI). The superior protection afforded by iFt-MHB compared to that of iFt-BHI was associated with significantly lower bacterial burden and inflammation in the lungs and spleens of vaccinated mice. Moreover, iFt-MHB also induced increased levels of Ft-specific IgG. Further evaluation of early immunological cues also revealed that iFt-MHB exhibits increased engagement of Ag-presenting cells including increased iFt binding to dendritic cells, increased expression of costimulatory markers, and increased secretion of pro-inflammatory cytokines. Importantly, these studies directly demonstrate that Ft growth conditions strongly impact Ft vaccine efficacy and that the growth medium used to produce whole cell vaccines to Ft must be a key consideration in the development of a tularemia vaccine.

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Section: Discussionmentioning

confidence: 99%

Differential Cultivation of Francisella tularensis Induces Changes in the Immune Response to and Protective Efficacy of Whole Cell-Based Inactivated Vaccines

et al. 2017

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“…5C highlights several genes relevant for activation, proliferation, and homeostasis of T cells that were significantly up-or downregulated through IL-7 treatment in DN T cells. Of interest, we found that predominantly genes that are necessary for maintaining an anergic state (30)(31)(32)(33) are downregulated in IL-7-treated DN T cells. The abrogated expression of anergy-controlling factors, such as FOXO, NFAT, EGR2, EGR3, and CBL, was verified by quantitative PCR (Fig.…”

Section: Transcriptome Analysis Identifies Key Downstream Network Ofmentioning

confidence: 96%

IL-7 Abrogates the Immunosuppressive Function of Human Double-Negative T Cells by Activating Akt/mTOR Signaling

Allgäuer

Schreiner

Ferrazzi

et al. 2015

The Journal of Immunology

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Recently, a novel subset of TCRαβ+ CD4− CD8− double-negative (DN) T cells was described to suppress immune responses in both mice and humans. Moreover, in murine models, infusion and/or activation of DN T cells specifically suppressed alloreactive T cells and prevented the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. We demonstrated that human DN T cells, like their murine counterparts, are highly potent suppressor cells of both CD4+ and CD8+ T cell responses. After hematopoietic stem cell transplantation and other lymphopenic conditions, IL-7 plays an important role in the reconstitution, survival, and homeostasis of the T cell compartment. Because IL-7 was shown to interfere with T cell functionality, we asked whether IL-7 affects the functionality of human DN T cells. Intriguingly, IL-7 diminished the suppressive activity of DN T cells toward allogeneic CD4+ effector T cells. Of interest, our studies revealed that IL-7 activates the Akt/mechanistic target of rapamycin (mTOR) pathway in human DN T cells. Importantly, selective inhibition of the protein kinases Akt or mTOR reversed the IL-7 effect, thereby restoring the functionality of DN T cells, whereas inhibition of other central T cell signaling pathways did not. Further analyses suggest that the IL-7/Akt/mTOR signaling cascade downregulates anergy-associated genes and upregulates activation- and proliferation-associated factors that may be crucial for DN T cell functionality. These findings indicate that IL-7 and Akt/mTOR signaling are critical factors for the suppressive capacity of DN T cells. Targeting of these pathways by pharmacological agents may restore and/or enhance DN T cell functionality in graft-versus-host disease.

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“…Because increased intracellular Ca 2+ levels in the absence of complete TCR signals are known to activate NFAT1, which can then activate anergy-inducing genes, we hypothesized that the reduced functionality of mir-150 −/− naïve CD8 + T cells might be associated with ectopic activation of NFAT1 in naïve mir-150 −/− CD8 + T cells 2, 5, 15 . Following incubation in physiological Ca 2+ concentrations, naïve mir-150 −/− CD8 + T cells showed increased nuclear localization of NFAT1 and active forms of NFAT1 (dephosphorylated NFAT1) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…TCR stimulation increases intracellular Ca 2+ concentrations, which induce the nuclear localization of nuclear factor of activated T-cells 1 (NFAT1) 2 . Simultaneously, CD28 co-stimulation activates mitogen-activated protein kinase, which activates activator protein 1 (AP-1).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-150 modulates intracellular Ca 2+ levels in naïve CD8+ T cells by targeting TMEM20

Kim

Jung

Seo

et al. 2017

Sci Rep

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Regulation of intracellular Ca2+ signaling is a major determinant of CD8+ T cell responsiveness, but the mechanisms underlying this regulation of Ca2+ levels, especially in naïve CD8+ T cells, are not fully defined. Here, we showed that microRNA-150 (miR-150) controls intracellular Ca2+ levels in naïve CD8+ T cells required for activation by suppressing TMEM20, a negative regulator of Ca2+ extrusion. miR-150 deficiency increased TMEM20 expression, which resulted in increased intracellular Ca2+ levels in naïve CD8+ T cells. The subsequent increase in Ca2+ levels induced expression of anergy-inducing genes, such as Cbl-b, Egr2, and p27, through activation of NFAT1, as well as reduced cell proliferation, cytokine production, and the antitumor activity of CD8+ T cells upon antigenic stimulation. The anergy-promoting molecular milieu and function induced by miR-150 deficiency were rescued by reinstatement of miR-150. Additionally, knockdown of TMEM20 in miR-150-deficient naïve CD8+ T cells reduced intracellular Ca2+ levels. Our findings revealed that miR-150 play essential roles in controlling intracellular Ca2+ level and activation in naïve CD8+ T cells, which suggest a mechanism to overcome anergy induction by the regulation of intracellular Ca2+ levels.

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Molecular mechanisms of T-cell anergy

Cited by 19 publications

References 155 publications

Differential Cultivation of Francisella tularensis Induces Changes in the Immune Response to and Protective Efficacy of Whole Cell-Based Inactivated Vaccines

Differential Cultivation of Francisella tularensis Induces Changes in the Immune Response to and Protective Efficacy of Whole Cell-Based Inactivated Vaccines

IL-7 Abrogates the Immunosuppressive Function of Human Double-Negative T Cells by Activating Akt/mTOR Signaling

MicroRNA-150 modulates intracellular Ca 2+ levels in naïve CD8+ T cells by targeting TMEM20

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