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

Nora V Lieske; Kristian Tonby; Dag Kvale; Anne M Dyrhol-Riise; Kjetil Tasken

doi:10.1371/journal.pone.0141903

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

PLoS One. 2015 Nov 6;10(11):e0141903. doi: 10.1371/journal.pone.0141903. eCollection 2015.

Authors

Nora V Lieske¹, Kristian Tonby^{2

3}, Dag Kvale^{2

3

4}, Anne M Dyrhol-Riise^{2

3

4}, Kjetil Tasken^{1

3

4

5}

Affiliations

¹ Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway.
² Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
³ Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway.
⁴ Kristian Gerhard Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
⁵ Biotechnology Centre, 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
CD4-Positive T-Lymphocytes / drug effects
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
Cytokines / metabolism
Female
Forkhead Transcription Factors / metabolism
HIV Infections / drug therapy*
HIV Infections / immunology
HIV Infections / pathology
Humans
Lymphocyte Activation / drug effects
MAP Kinase Signaling System / drug effects*
Male
Middle Aged
Molecular Targeted Therapy*
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use
T-Lymphocytes, Regulatory / drug effects*
T-Lymphocytes, Regulatory / immunology
T-Lymphocytes, Regulatory / metabolism
Tuberculosis / drug therapy*
Tuberculosis / immunology
Tuberculosis / pathology
Up-Regulation / drug effects
Young Adult

Substances

Cytokines
FOXP3 protein, human
Forkhead Transcription Factors
Protein Kinase Inhibitors

Grants and funding

This work was supported by the Research Council of Norway (RCN204784 and RCN187615, http://www.forskningsradet.no/en/Home_page/1177315753906, N.L., Kj.T.), the South Eastern Norway Regional Health Authority (11/01137-144 and 2013074, http://www.helse-sorost.no/omoss_/english_/, Kr.T and Kj.T respectively) and the Kristian Gerhard Jebsen Inflammation Research Centre (2012/23, http://www.stiftkgj.no/?lang=en, K.T.).