The transcription factors Runx3 and ThPOK cross-regulate acquisition of cytotoxic function by human Th1 lymphocytes
- Université Libre de Bruxelles, Belgium
- Aix Marseille Univ, CNRS, INSERM U1104, France
- Ragon Institute of MGH, MIT and Harvard, United States
- Sanquin Research and Landsteiner Laboratory AMC/UvA, Netherlands
Abstract
Cytotoxic CD4 (CD4CTX) T cells are emerging as an important component of anti-viral and anti-tumor immunity but the molecular basis of their development remains poorly understood. In the context of human cytomegalovirus infection, a significant proportion of CD4 T cells displays cytotoxic functions. We observed that the transcriptional program of these cells was enriched in CD8 T cell lineage genes despite the absence of ThPOK downregulation. We further show that establishment of CD4CTX-specific transcriptional and epigenetic programs occurred in a stepwise fashion along the Th1-differentiation pathway. In vitro, prolonged activation of naive CD4 T cells in presence of Th1 polarizing cytokines led to the acquisition of perforin-dependent cytotoxic activity. This process was dependent on the Th1 transcription factor Runx3 and was limited by the sustained expression of ThPOK. This work elucidates the molecular program of human CD4CTX T cells and identifies potential targets for immunotherapy against viral infections and cancer.
Data availability
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Genome-wide study of transcriptional and methylation profile of human cytotoxic CD4 T cellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE75406).
Article and author information
Author details
Thien-Phong Vu Manh
Funding
Fonds De La Recherche Scientifique - FNRS (PhD Student Fellowship)
- Yasmina Serroukh
Belgian Federal Public Planning Service Science Policy (Research Project Grant)
- Stanislas Goriely
- Arnaud Marchant
European Regional Development Fund and Walloon Region (Research Project Grant (411132-957270))
- Stanislas Goriely
- Arnaud Marchant
Fonds De La Recherche Scientifique - FNRS (Research Project Grant (PDR))
- François Fuks
- Stanislas Goriely
- Arnaud Marchant
Fonds Erasme (PhD Student Fellowship)
- Alice Hoyois
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Ronald N Germain, National Institute of Allergy and Infectious Diseases, United States
Ethics
Human subjects: Volunteers were recruited by the research centre ImmuneHealth, CHU Tivoli, La Louvière. Clinical staff informed the volunteers about the objectives of the study and obtained their written consent to use the human material for research purposes. The study and the informed consent form were approved , following approval by the Ethics committee of the CHU Tivoli, La Louvière, Belgium (Reference B09620097253). The study followed the Good Clinical Practice (ICH/GCP) guidelines, the Belgian Law and the declaration of Helsinki ("World Medical Association Declaration of Helsinki; Ethical Principles for Medical Research Involving Human Subjects").
Version history
- Received: July 18, 2017
- Accepted: February 20, 2018
- Accepted Manuscript published: February 28, 2018 (version 1)
- Version of Record published: March 9, 2018 (version 2)
Copyright
© 2018, Serroukh et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The transcription factors Runx3 and ThPOK cross-regulate acquisition of cytotoxic function by human Th1 lymphocytes
eLife 7:e30496.
https://doi.org/10.7554/eLife.30496
Further reading
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- Immunology and Inflammation
- Medicine
Background:
Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin.
Methods:
Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors.
Results:
We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01–2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004).
Conclusions:
Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin.
Funding:
LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).
Clinical trial number:
-
- Immunology and Inflammation
Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as arachidonate 5-lipoxygenase (ALOX5) and ALOX5 activating protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6 days training, they exhibit enhanced TNF-α and IL-6 production to lipopolysaccharide (LPS). Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients.
