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Cytotoxicity is the capacity for immune cells to kill infected or malignant cells in order to eliminate pathogens and tumours through different mechanisms including the exocytosis of perforin-containing cytosolic granules. This crucial property is usually restricted to specialized innate and adaptive lymphocytes such as natural killer (NK) cells and CD8 T cells. T lymphocytes differentiate in the thymus and are delivered to the peripheral blood as naive T cells committed to either the CD8 or the CD4 lineage. CD8 T cells are programmed to acquire cytotoxic effector functions under the control of the transcription factor (TF) Runx3. The fate of CD4 T cells is to acquire multiple helper functions through the action of the TF ThPOK that promotes CD4 helper functions and restricts the CD8 cytotoxic program. However, this restriction is not absolute as cytotoxic CD4 (CD4CTX) T cells differentiate in vivo, indicating that the multipotency of human naive CD4 T cells includes the ability to acquire perforin expression and potent cytotoxicity in vitro and ex vivo. This cytotoxic potential correlates with outcome in human pathology and mediates protection against viral challenge and tumour eradication in murine models. CD4CTX T cells are terminally differentiated effector memory T cells that accumulate during cytomegalovirus chronic infection and ageing. They are phenotypically and functionally related to T helper type 1 (Th1)-effector memory cells. However, whether they belong to the Th1 pathway or constitute a separate specialized helper T cell subset is unknown. In this work, we show that CD4CTX T cell differentiation is an integral part of the Th1 pathway. Indeed, CD4 T cells acquire cytotoxic potential early in the memory differentiation process as central memory Th1 but not Th2 and Th17 cells are epigenetically primed to develop a cytotoxic program. The expression of perforin and other cytotoxic genes present a stepwise increase profile that is specific of the Th1 differ, Doctorat en Sciences médicales (Médecine), info:eu-repo/semantics/nonPublished