Cargando…
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 re...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636186/ https://www.ncbi.nlm.nih.gov/pubmed/26544592 http://dx.doi.org/10.1371/journal.pone.0141903 |
_version_ | 1782399615072468992 |
---|---|
author | Lieske, Nora V. Tonby, Kristian Kvale, Dag Dyrhol-Riise, Anne M. Tasken, Kjetil |
author_facet | Lieske, Nora V. Tonby, Kristian Kvale, Dag Dyrhol-Riise, Anne M. Tasken, Kjetil |
author_sort | Lieske, Nora V. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4636186 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-46361862015-11-13 Targeting Tuberculosis and HIV Infection-Specific Regulatory T Cells with MEK/ERK Signaling Pathway Inhibitors Lieske, Nora V. Tonby, Kristian Kvale, Dag Dyrhol-Riise, Anne M. Tasken, Kjetil PLoS One Research Article 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. Public Library of Science 2015-11-06 /pmc/articles/PMC4636186/ /pubmed/26544592 http://dx.doi.org/10.1371/journal.pone.0141903 Text en © 2015 Lieske et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Lieske, Nora V. Tonby, Kristian Kvale, Dag Dyrhol-Riise, Anne M. Tasken, Kjetil Targeting Tuberculosis and HIV Infection-Specific Regulatory T Cells with MEK/ERK Signaling Pathway Inhibitors |
title | Targeting Tuberculosis and HIV Infection-Specific Regulatory T Cells with MEK/ERK Signaling Pathway Inhibitors |
title_full | Targeting Tuberculosis and HIV Infection-Specific Regulatory T Cells with MEK/ERK Signaling Pathway Inhibitors |
title_fullStr | Targeting Tuberculosis and HIV Infection-Specific Regulatory T Cells with MEK/ERK Signaling Pathway Inhibitors |
title_full_unstemmed | Targeting Tuberculosis and HIV Infection-Specific Regulatory T Cells with MEK/ERK Signaling Pathway Inhibitors |
title_short | Targeting Tuberculosis and HIV Infection-Specific Regulatory T Cells with MEK/ERK Signaling Pathway Inhibitors |
title_sort | targeting tuberculosis and hiv infection-specific regulatory t cells with mek/erk signaling pathway inhibitors |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636186/ https://www.ncbi.nlm.nih.gov/pubmed/26544592 http://dx.doi.org/10.1371/journal.pone.0141903 |
work_keys_str_mv | AT lieskenorav targetingtuberculosisandhivinfectionspecificregulatorytcellswithmekerksignalingpathwayinhibitors AT tonbykristian targetingtuberculosisandhivinfectionspecificregulatorytcellswithmekerksignalingpathwayinhibitors AT kvaledag targetingtuberculosisandhivinfectionspecificregulatorytcellswithmekerksignalingpathwayinhibitors AT dyrholriiseannem targetingtuberculosisandhivinfectionspecificregulatorytcellswithmekerksignalingpathwayinhibitors AT taskenkjetil targetingtuberculosisandhivinfectionspecificregulatorytcellswithmekerksignalingpathwayinhibitors |