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.
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.
Metrics
-
- 4,075
- views
-
- 484
- downloads
-
- 55
- 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
-
- Evolutionary Biology
- Immunology and Inflammation
CD4+ T cell activation is driven by five-module receptor complexes. The T cell receptor (TCR) is the receptor module that binds composite surfaces of peptide antigens embedded within MHCII molecules (pMHCII). It associates with three signaling modules (CD3γε, CD3δε, and CD3ζζ) to form TCR-CD3 complexes. CD4 is the coreceptor module. It reciprocally associates with TCR-CD3-pMHCII assemblies on the outside of a CD4+ T cells and with the Src kinase, LCK, on the inside. Previously, we reported that the CD4 transmembrane GGXXG and cytoplasmic juxtamembrane (C/F)CV+C motifs found in eutherian (placental mammal) CD4 have constituent residues that evolved under purifying selection (Lee et al., 2022). Expressing mutants of these motifs together in T cell hybridomas increased CD4-LCK association but reduced CD3ζ, ZAP70, and PLCγ1 phosphorylation levels, as well as IL-2 production, in response to agonist pMHCII. Because these mutants preferentially localized CD4-LCK pairs to non-raft membrane fractions, one explanation for our results was that they impaired proximal signaling by sequestering LCK away from TCR-CD3. An alternative hypothesis is that the mutations directly impacted signaling because the motifs normally play an LCK-independent role in signaling. The goal of this study was to discriminate between these possibilities. Using T cell hybridomas, our results indicate that: intracellular CD4-LCK interactions are not necessary for pMHCII-specific signal initiation; the GGXXG and (C/F)CV+C motifs are key determinants of CD4-mediated pMHCII-specific signal amplification; the GGXXG and (C/F)CV+C motifs exert their functions independently of direct CD4-LCK association. These data provide a mechanistic explanation for why residues within these motifs are under purifying selection in jawed vertebrates. The results are also important to consider for biomimetic engineering of synthetic receptors.
-
- Genetics and Genomics
- Immunology and Inflammation
Transposable elements (TEs) are repetitive sequences representing ~45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTECs). In this study, we investigated the role of TEs on T-cell development in the thymus. We performed multiomic analyses of TEs in human and mouse thymic cells to elucidate their role in T-cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TE expression correlates with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDCs). In mTECs, transcriptomic data suggest that TEs interact with transcription factors essential for mTEC development and function (e.g., PAX1 and REL), and immunopeptidomic data showed that TEs generate MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 regulate small yet non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large numbers of TEs that likely form dsRNA, which can activate innate immune receptors, potentially explaining why thymic pDCs constitutively secrete IFN ɑ/β. This study highlights the diversity of interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. Therefore, we propose that orchestrating TE expression in thymic cells is critical to prevent autoimmunity in vertebrates.
