Laury Nguema, Yves Lévy, Véronique Godot
The fields of vaccinology and tumor immunology have long prioritized CD8+ central memory T (Tcm) cells as markers of long-term protection, often neglecting the cell population responsible for the most durable immune memory. Recent advances in T cell biology have clearly established the existence of stem cell-like memory T (Tscm) lymphocytes, now regarded as major emerging contributors. CD8+ Tscm cells are highlighted for their capacity for long-term self-renewal, multipotency, and robust recall responses, features that make them attractive targets in chronic infection and cancer immunotherapy. The real revolution is mechanistic: Tscm cell differentiation follows a defined blueprint integrating a specific metabolic profile, lymphoid niche control, and the T cell receptor (TCR) "Goldilocks principle," tuned by costimulatory networks. This review synthesizes current mechanistic knowledge of Tscm cell induction and discusses how it can guide the rational design of future vaccines and adoptive cell therapies engineered to generate these long-lived populations.