Developmental characterization of Group 1 Innate Lymphoid Cells: from mouse to human

Natural Killer (NK) cells are a heterogeneous population of cytotoxic cells that can be grouped in phenotypically and functionally different subsets. Among them, human CD56bright and CD56dim NK cells show important differences in their cytotoxic activity, cytokine production, and responses to cytokine activation. Moreover, CD56bright NK cells differ from CD56dim ones for the phenotypic expression of CD117, CD16 and the HLA class I inhibitory receptors (CD94/NKG2A and KIRs). CD56bright NK cells have been proposed to represent either a mature NK cell subpopulation or an immature stage of the CD56dim NK subset. Considered that CD56bright/CD16dim/neg NK cells are virtually all licensed by CD94-NKG2A expression, it is not clear which subset represents the real immature stage of the licensed CD56dimCD16bright NK cells. Human CD56bright NK cells are thought to be the counterpart of mouse thymic NK (tNK) cells, because they share some characteristics like the requirement for GATA3 and the dependence on IL-7, but it is not completely clear weather they are NK cells or a different subset of Group 1 Innate Lymphoid Cells (Group 1 ILCs); in fact tNK cells have been described with hybrid features of immature NK cells and ILC1. We have investigated the mechanisms governing tNK cell functions, demonstrating that tNK cells express the transcription factor EOMES and that they developed independent of the essential ILC1 factor TBET, confirming their placement within the NK lineage. Moreover, tNK cells developed independent of the E protein transcription factor inhibitor ID2 and their numbers were only mildly affected by the loss of ETS1. Our data revealed that in the thymus of mice there is an absence of ILC1, setting the stage for deeper studies of the relationship between murine tNK cells and human CD56bright NK cells. In the first part of this project, using culture systems capable of generating CD56bright and CD56dim NK cells from the human hematopoietic progenitors CD34+ circulating in the peripheral blood through the administration of appropriate cytokine combinations, we have been able to characterize the differentiating NK cells. Thus, we indicate that CD56dim and CD56bright NK cells, would originate from distinct progenitors, which, along with their differentiation into mature cells, would generate two distinct cell NK subsets with convergent phenotypes and functions. Moreover, during their development CD56dim and CD56bright NK cells would exploit different mechanisms to prevent cytotoxicity against healthy cells. .