T-cells are an essential component of the immune system that provide protection against pathogen infections and cancer and are involved in the aetiology of numerous autoimmune and autoinflammatory pathologies. Their importance in disease, the relative ease to isolate, expand and manipulate them ex vivo have put T-cells at the forefront of basic and translational research in immunology. Decades of study have shed some light on the unique way T-cells integrate extrinsic environmental cues influencing an activation program triggered by interactions between peptide-MHC complexes and the antigen-recognition machinery constituted of clonally distributed T-cell receptors and their co-receptor CD4 or CD8. The manipulation of these molecular determinants in cellular systems or as recombinant proteins has considerably enhanced our ability to understand antigen-specific T-cell activation, to monitor ongoing T-cell responses and to exploit T-cells for therapy. Even though these principles have given numerous insights in the biology of CD8+ T-cells that translate into promising therapeutic prospects, as illustrated by recent breakthroughs in cancer therapy, they have proven more challenging to apply to CD4+ T-cells. This Research Topics aims to provide a comprehensive view of the recent insights provided by the use of engineered antigen receptors and their ligands on T-cell activation and how they have been or could be harnessed to design efficient immunotherapies.