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.
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.
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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
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The members of the Mycobacterium tuberculosis complex (MTBC) causing human tuberculosis comprise 10 phylogenetic lineages that differ in their geographical distribution. The human consequences of this phylogenetic diversity remain poorly understood. Here, we assessed the phenotypic properties at the host-pathogen interface of 14 clinical strains representing five major MTBC lineages. Using a human in vitro granuloma model combined with bacterial load assessment, microscopy, flow cytometry, and multiplexed-bead arrays, we observed considerable intra-lineage diversity. Yet, modern lineages were overall associated with increased growth rate and more pronounced granulomatous responses. MTBC lineages exhibited distinct propensities to accumulate triglyceride lipid droplets—a phenotype associated with dormancy—that was particularly pronounced in lineage 2 and reduced in lineage 3 strains. The most favorable granuloma responses were associated with strong CD4 and CD8 T cell activation as well as inflammatory responses mediated by CXCL9, granzyme B, and TNF. Both of which showed consistent negative correlation with bacterial proliferation across genetically distant MTBC strains of different lineages. Taken together, our data indicate that different virulence strategies and protective immune traits associate with MTBC genetic diversity at lineage and strain level.
