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Targeting Tuberculosis and HIV Infection-Specific Regulatory T Cells with MEK/ERK Signaling Pathway Inhibitors.

Lieske NV, Tonby K, Kvale D, Dyrhol-Riise AM, Tasken K - PLoS ONE (2015)

Bottom Line: Stimulation of T cells from untreated TB (n = 12) and HIV (n = 8) patients with disease-specific antigens in vitro in the presence of the MEK inhibitor (MEKI) trametinib (GSK1120212) resulted in significant down-regulation of both FoxP3 levels (MFI) and fractions of resting (CD45RA+FoxP3+) and activated (CD45RA-FoxP3++) Tregs.MEKI also reduced the levels of specific T effector cells expressing the pro-inflammatory cytokines (IFN-γ, TNF-α and IL-2) in both HIV and TB patients.Whether MEKIs can be used in current HIV or TB therapy regimens needs to be further investigated.

View Article: PubMed Central - PubMed

Affiliation: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway.

ABSTRACT
Human regulatory T cells (Tregs) are essential in maintaining immunological tolerance and suppress effector T cells. Tregs are commonly up-regulated in chronic infectious diseases such as tuberculosis (TB) and human immunodeficiency virus (HIV) infection and thereby hamper disease-specific immune responses and eradication of pathogens. The MEK/ERK signaling pathway is involved in regulation of the FoxP3 transcription factor, which directs a lineage-specific transcriptional program to define Tregs and control their suppressive function. Here, we aimed to target activation of disease-specific Tregs by inhibition of the MEK/ERK signaling pathway based on the hypothesis that this would improve anti-HIV and anti-TB immunity. Stimulation of T cells from untreated TB (n = 12) and HIV (n = 8) patients with disease-specific antigens in vitro in the presence of the MEK inhibitor (MEKI) trametinib (GSK1120212) resulted in significant down-regulation of both FoxP3 levels (MFI) and fractions of resting (CD45RA+FoxP3+) and activated (CD45RA-FoxP3++) Tregs. MEKI also reduced the levels of specific T effector cells expressing the pro-inflammatory cytokines (IFN-γ, TNF-α and IL-2) in both HIV and TB patients. In conclusion, MEKIs modulate disease antigen-specific Treg activation and may have potential application in new treatment strategies in chronic infectious diseases where reduction of Treg activity would be favorable. Whether MEKIs can be used in current HIV or TB therapy regimens needs to be further investigated.

No MeSH data available.


Related in: MedlinePlus

Effect of HIV antigen and MEK inhibition on FoxP3 expression in resting and activated Tregs in HIV patient samples.(a) Gating strategy for resting (CD4+CD45RA+FoxP3+) and activated (CD4+CD45RA-FoxP3++) Tregs. (b) PBMCs were stimulated with Gag (grey boxes) or Env (white boxes) for 36 h in presence or absence of MEK inhibitor GSK1120212 or left untreated. Effect of GSK1120212 (100 nM and 10 μM) on FoxP3 expression levels (MFI) (c, e) and number of FoxP3+ T cells (d, f) in rTregs (c, d) and aTregs (e, f) stimulated with Gag or Env. (g) Ratio of aTreg over rTreg (%) in samples stimulated with Gag or Env alone and at two different MEKI concentrations as in d and e. (Boxes: median ± 25th to 75th percentile; whiskers: min to max, n = 8,* p< 0.05, **p <0.01).
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pone.0141903.g004: Effect of HIV antigen and MEK inhibition on FoxP3 expression in resting and activated Tregs in HIV patient samples.(a) Gating strategy for resting (CD4+CD45RA+FoxP3+) and activated (CD4+CD45RA-FoxP3++) Tregs. (b) PBMCs were stimulated with Gag (grey boxes) or Env (white boxes) for 36 h in presence or absence of MEK inhibitor GSK1120212 or left untreated. Effect of GSK1120212 (100 nM and 10 μM) on FoxP3 expression levels (MFI) (c, e) and number of FoxP3+ T cells (d, f) in rTregs (c, d) and aTregs (e, f) stimulated with Gag or Env. (g) Ratio of aTreg over rTreg (%) in samples stimulated with Gag or Env alone and at two different MEKI concentrations as in d and e. (Boxes: median ± 25th to 75th percentile; whiskers: min to max, n = 8,* p< 0.05, **p <0.01).

Mentions: Since T cell activation varies substantially between HIV-infected patients and even within a given patient depending on stimulation with matrix (Gag) or envelope (Env) antigens, the effect of MEKIs on Treg activation was assessed separately in Gag or Env stimulated HIV samples (Figs 4 and 5). Moreover, two different concentrations of the MEKI GSK1120212 were tested. FoxP3 levels in rTregs decreased after stimulation in presence of MEKI at 10μM (p < 0.01) in Gag stimulated cells and at 100nM (p <0.01) in Env stimulated cells (Fig 4c). The percentage of rTregs decreased significantly after Env stimulation at both MEKI concentrations (p < 0.05), but not after Gag stimulation (Fig 4d). Similarly, FoxP3 levels in aTregs decreased significantly after Env stimulation at both MEKI concentrations (p <0.05), but not after Gag stimulation (Fig 4e). In contrast, the percentage of aTregs decreased significantly in both Gag- and Env stimulated samples at both MEKI concentrations (Fig 4f) as did the aTreg/rTreg ratios (Fig 4g).


Targeting Tuberculosis and HIV Infection-Specific Regulatory T Cells with MEK/ERK Signaling Pathway Inhibitors.

Lieske NV, Tonby K, Kvale D, Dyrhol-Riise AM, Tasken K - PLoS ONE (2015)

Effect of HIV antigen and MEK inhibition on FoxP3 expression in resting and activated Tregs in HIV patient samples.(a) Gating strategy for resting (CD4+CD45RA+FoxP3+) and activated (CD4+CD45RA-FoxP3++) Tregs. (b) PBMCs were stimulated with Gag (grey boxes) or Env (white boxes) for 36 h in presence or absence of MEK inhibitor GSK1120212 or left untreated. Effect of GSK1120212 (100 nM and 10 μM) on FoxP3 expression levels (MFI) (c, e) and number of FoxP3+ T cells (d, f) in rTregs (c, d) and aTregs (e, f) stimulated with Gag or Env. (g) Ratio of aTreg over rTreg (%) in samples stimulated with Gag or Env alone and at two different MEKI concentrations as in d and e. (Boxes: median ± 25th to 75th percentile; whiskers: min to max, n = 8,* p< 0.05, **p <0.01).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4636186&req=5

pone.0141903.g004: Effect of HIV antigen and MEK inhibition on FoxP3 expression in resting and activated Tregs in HIV patient samples.(a) Gating strategy for resting (CD4+CD45RA+FoxP3+) and activated (CD4+CD45RA-FoxP3++) Tregs. (b) PBMCs were stimulated with Gag (grey boxes) or Env (white boxes) for 36 h in presence or absence of MEK inhibitor GSK1120212 or left untreated. Effect of GSK1120212 (100 nM and 10 μM) on FoxP3 expression levels (MFI) (c, e) and number of FoxP3+ T cells (d, f) in rTregs (c, d) and aTregs (e, f) stimulated with Gag or Env. (g) Ratio of aTreg over rTreg (%) in samples stimulated with Gag or Env alone and at two different MEKI concentrations as in d and e. (Boxes: median ± 25th to 75th percentile; whiskers: min to max, n = 8,* p< 0.05, **p <0.01).
Mentions: Since T cell activation varies substantially between HIV-infected patients and even within a given patient depending on stimulation with matrix (Gag) or envelope (Env) antigens, the effect of MEKIs on Treg activation was assessed separately in Gag or Env stimulated HIV samples (Figs 4 and 5). Moreover, two different concentrations of the MEKI GSK1120212 were tested. FoxP3 levels in rTregs decreased after stimulation in presence of MEKI at 10μM (p < 0.01) in Gag stimulated cells and at 100nM (p <0.01) in Env stimulated cells (Fig 4c). The percentage of rTregs decreased significantly after Env stimulation at both MEKI concentrations (p < 0.05), but not after Gag stimulation (Fig 4d). Similarly, FoxP3 levels in aTregs decreased significantly after Env stimulation at both MEKI concentrations (p <0.05), but not after Gag stimulation (Fig 4e). In contrast, the percentage of aTregs decreased significantly in both Gag- and Env stimulated samples at both MEKI concentrations (Fig 4f) as did the aTreg/rTreg ratios (Fig 4g).

Bottom Line: Stimulation of T cells from untreated TB (n = 12) and HIV (n = 8) patients with disease-specific antigens in vitro in the presence of the MEK inhibitor (MEKI) trametinib (GSK1120212) resulted in significant down-regulation of both FoxP3 levels (MFI) and fractions of resting (CD45RA+FoxP3+) and activated (CD45RA-FoxP3++) Tregs.MEKI also reduced the levels of specific T effector cells expressing the pro-inflammatory cytokines (IFN-γ, TNF-α and IL-2) in both HIV and TB patients.Whether MEKIs can be used in current HIV or TB therapy regimens needs to be further investigated.

View Article: PubMed Central - PubMed

Affiliation: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway.

ABSTRACT
Human regulatory T cells (Tregs) are essential in maintaining immunological tolerance and suppress effector T cells. Tregs are commonly up-regulated in chronic infectious diseases such as tuberculosis (TB) and human immunodeficiency virus (HIV) infection and thereby hamper disease-specific immune responses and eradication of pathogens. The MEK/ERK signaling pathway is involved in regulation of the FoxP3 transcription factor, which directs a lineage-specific transcriptional program to define Tregs and control their suppressive function. Here, we aimed to target activation of disease-specific Tregs by inhibition of the MEK/ERK signaling pathway based on the hypothesis that this would improve anti-HIV and anti-TB immunity. Stimulation of T cells from untreated TB (n = 12) and HIV (n = 8) patients with disease-specific antigens in vitro in the presence of the MEK inhibitor (MEKI) trametinib (GSK1120212) resulted in significant down-regulation of both FoxP3 levels (MFI) and fractions of resting (CD45RA+FoxP3+) and activated (CD45RA-FoxP3++) Tregs. MEKI also reduced the levels of specific T effector cells expressing the pro-inflammatory cytokines (IFN-γ, TNF-α and IL-2) in both HIV and TB patients. In conclusion, MEKIs modulate disease antigen-specific Treg activation and may have potential application in new treatment strategies in chronic infectious diseases where reduction of Treg activity would be favorable. Whether MEKIs can be used in current HIV or TB therapy regimens needs to be further investigated.

No MeSH data available.


Related in: MedlinePlus