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

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.

Below:  Effect of MEK inhibition on FoxP3 expression in sorted resting Tregs (rTregs). Human blood donor rTregs were stimulated with anti-CD3/CD28/CD2-coated MACSiBeads for 36 h in the presence or absence of MEK specific inhibitors (MEKI), followed by FoxP3 staining and FACS analysis. (a) Gating strategy for sorting of rTregs from CD4+ enriched cells. (b) rTregs were stimulated in the presence or absence of the MEK specific inhibitor GSK1120212 or left unstimulated. (c) rTregs were stimulated in presence or absence of the different MEK specific inhibitors FR180204, PD098059, U0126, CI-1040, AZD6244, PD0325901, MEK162, GSK1120212 at 1μM concentration. (d and e) Concentration-dependent effect of PD0325901 (IC50 = 17 nM) and GSK1120212 (IC50 = 4 nM). c-e: mean ± SD (n = 3).

Full article at: http://goo.gl/fq4eq2

By:

Nora V. Lieske, Kjetil Tasken

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

Kristian Tonby, Dag Kvale, Anne M. Dyrhol-Riise

Institute of Clinical Medicine, University of Oslo, Oslo, Norway

Kristian Tonby, Dag Kvale, Anne M. Dyrhol-Riise, Kjetil Tasken

Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway

Dag Kvale, Anne M. Dyrhol-Riise, Kjetil Tasken

Kristian Gerhard Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway

Kjetil Tasken

Biotechnology Centre, University of Oslo, Oslo, Norway

  

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