Ragon Institute of MGH, MIT and Harvard University, Cambridge, United States; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States
Martin Bizet
Laboratoire d’Epigénétique du Cancer, Université Libre de Bruxelles, Bruxelles, Belgium
Emeline Pollet
Centre d’Immunologie de Marseille-Luminy 13288, Aix Marseille Université UM2, Marseille, France
Tressy Tabbuso
Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium
Emilie Calonne
Laboratoire d’Epigénétique du Cancer, Université Libre de Bruxelles, Bruxelles, Belgium
Klaas van Gisbergen
Department of Haematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam, Netherlands
Marc Dalod
Centre d’Immunologie de Marseille-Luminy 13288, Aix Marseille Université UM2, Marseille, France
François Fuks
Laboratoire d’Epigénétique du Cancer, Université Libre de Bruxelles, Bruxelles, Belgium
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.
