CD8 cytotoxic T cells are generated in the thymus upon a series of developmental selection processes that render them self-MHC/peptide reactive but also self-tolerant. The full maturation and acquisition of cytolytic effector function are thought to happen only after their export into and upon antigen encounter in peripheral tissues. Contrary to these conventional CD8 T cells, innate CD8 T cells acquire their effector function during their development in the thymus and prior to immune activation by foreign antigens [1]. Thus, innate CD8 T cells have been considered critical for establishing immediate-early immune response, but they also pose a risk of overt immune reaction and autoimmunity as they are already highly activated and proinflammatory under steady-state conditions. Consequently, the frequency and number of innate CD8 T cells are strictly controlled, and multiple mechanisms have been proposed to regulate and determine their abundance [1].

While their developmental pathway remains incompletely mapped, we previously documented a role of the γc cytokine receptor in promoting the generation of innate CD8 T cells [2]. Here, we expand on this observation, and we document that increased γc expression expands the pool of innate CD8 T cells through increased thymic selection and not by proliferation. Moreover, such γc-driven increase of innate CD8 T cell number was not restricted to classical MHC-I molecules, documenting a fundamental difference in their MHC-specificity and cytokine requirement to conventional CD8 T cells. These findings set the stage for further studies into assessing the distinct antigen reactivity and functional divergence of innate CD8 T cells.