The transcription factors Runx3 and ThPOK cross-regulate acquisition of cytotoxic function by human Th1 lymphocytes

Elife. 2018 Feb 28;7:e30496. doi: 10.7554/eLife.30496.


Cytotoxic CD4 (CD4CTX) T cells are emerging as an important component of antiviral and antitumor 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.

Keywords: Runx3; T-bet; Th1 differentiation; ThPOK; cytomegalovirus; cytotoxic CD4 T cell; human; immunology; inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cell Differentiation*
  • Cells, Cultured
  • Core Binding Factor Alpha 3 Subunit / metabolism*
  • Cytomegalovirus Infections / immunology*
  • DNA-Binding Proteins / metabolism*
  • Female
  • Gene Expression Regulation
  • Humans
  • Male
  • Mice
  • Middle Aged
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocytes, Cytotoxic / immunology*
  • Th1 Cells / immunology*
  • Transcription Factors / metabolism*


  • Core Binding Factor Alpha 3 Subunit
  • DNA-Binding Proteins
  • Runx3 protein, human
  • Transcription Factors
  • ZBTB7B protein, human

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.