T lymphocytes mediate specific and long-lasting immunity to microbial pathogens. This kind of immunity is called adaptive immunity. Adaptive immunity is typically slow. This contrasts to macrophages and NK cells which protect in a more general, less specific manner. This immunity, called innate immunity, is immediately available. We recently described a T cell lineage which has characteristics of both types of immunity. The cells carry a specific T cell receptor (TCR) and express receptors that are present on macrophages and NK cells. Furthermore, these T cells are activated and ready for action. We call these T cells KIR+ Helios+ unconventional T cells (UTCs). Two UTC lineages have been described earlier: the MAIT and NKT lineage. Both these lineages express an invariant TCR directed against bacterial structures. In the present project, we aim to identify the ligands that activate these KIR+ Helios+ UTCs. Our strategy is based on the hypothesis that the TCRs are reactive to antigens present during their differentiation from stem cells. As the TCR repertoire is polyclonal, we expect a diverse set of ligands. Therefore, we will experimentally generate UTC populations with a monomorphic TCR. Subsequently, the populations will be assayed for reactivity against structures present in vitro or in vivo murine model for differentiation of UTCs. The knowledge of the nature of the ligands that activate the KIR+Helios+ UTC lineage is crucial to understand their role in human immunity.