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
-
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.
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").
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.
Metrics
-
- 4,316
- views
-
- 502
- downloads
-
- 61
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
-
- Immunology and Inflammation
The T6SS of Pseudomonas aeruginosa plays an essential role in the establishment of chronic infections. Inflammasome-mediated inflammatory cytokines are crucial for host defense against bacterial infections. We found that P. aeruginosa infection activates the non-canonical inflammasome in macrophages, yet it inhibits the downstream activation of the NLRP3 inflammasome. The VgrG2b of P. aeruginosa is recognized and cleaved by caspase-11, generating a free C-terminal fragment. The VgrG2b C-terminus can bind to NLRP3, inhibiting the activation of the NLRP3 inflammasome by rejecting NEK7 binding to NLRP3. Administration of a specific peptide that inhibits caspase-11 cleavage of VgrG2b significantly improves mouse survival during infection. Our discovery elucidates a mechanism by which P. aeruginosa inhibits host immune response, providing a new approach for the future clinical treatment of P. aeruginosa infections.
-
- Immunology and Inflammation
- Medicine
Preterm infants are susceptible to neonatal sepsis, a syndrome of pro-inflammatory activity, organ damage, and altered metabolism following infection. Given the unique metabolic challenges and poor glucose regulatory capacity of preterm infants, their glucose intake during infection may have a high impact on the degree of metabolism dysregulation and organ damage. Using a preterm pig model of neonatal sepsis, we previously showed that a drastic restriction in glucose supply during infection protects against sepsis via suppression of glycolysis-induced inflammation, but results in severe hypoglycemia. Now we explored clinically relevant options for reducing glucose intake to decrease sepsis risk, without causing hypoglycemia and further explore the involvement of the liver in these protective effects. We found that a reduced glucose regime during infection increased survival via reduced pro-inflammatory response, while maintaining normoglycemia. Mechanistically, this intervention enhanced hepatic oxidative phosphorylation and possibly gluconeogenesis, and dampened both circulating and hepatic inflammation. However, switching from a high to a reduced glucose supply after the debut of clinical symptoms did not prevent sepsis, suggesting metabolic conditions at the start of infection are key in driving the outcome. Finally, an early therapy with purified human inter-alpha inhibitor protein, a liver-derived anti-inflammatory protein, partially reversed the effects of low parenteral glucose provision, likely by inhibiting neutrophil functions that mediate pathogen clearance. Our findings suggest a clinically relevant regime of reduced glucose supply for infected preterm infants could prevent or delay the development of sepsis in vulnerable neonates.
