title: Targeting Tuberculosis and HIV Infection-Specific Regulatory T Cells with MEK/ERK Signaling Pathway Inhibitors.
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.
authors.affiliation: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway.
authors.forename: Nora V
authors.initials: NV
authors.lastname: Lieske
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway.
authors.forename: Kristian
authors.initials: K
authors.lastname: Tonby
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway.|Kristian Gerhard Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
authors.forename: Dag
authors.initials: D
authors.lastname: Kvale
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway.|Kristian Gerhard Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Dyrhol-Riise
authors.affiliation: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway.|Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway.|Kristian Gerhard Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.|Biotechnology Centre, University of Oslo, Oslo, Norway.
authors.forename: Kjetil
authors.initials: K
authors.lastname: Tasken
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects; D055815:Young Adult
chemical_list: D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D047428:Protein Kinase Inhibitors