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Differentiation and role of Natural Killer cell subsets

Final Report Summary - DIRONAKI (Differentiation and role of Natural Killer cell subsets)

Natural Killer (NK) cells are lymphocytes of the immune system that patrol the body and fight against viral infections and spontaneous tumors at early stages. They are equipped with an unique molecular arsenal that allow them to recognize and kill abnormal cells. This project was designed to better understand how these particular cells arise in the body and how they become specialized to achieve their function. We engineered several transgenic mouse models that helped us reporting on the expression and function of various genes suspected to be important for NK cells. This allowed us to demonstrate that 1) the expression of the Eomes transcription factor is a hallmark of this lineage and is a likely master regulator of the effector program of this cell type; 2) Zeb2 is another transcription factor that helps specifying the identity of the NK cell lineage at late stages of maturation; 3) TGF-b is a negative regulator of NK cell development, likely favoring the development of ILC1s, a closely related cell type that we contributed to describe in the liver and other tissues. TGFb negatively regulates NK cell bioenergetics metabolism. 4) peripheral NK cells are heterogeneous, including several subsets that correspond to discrete stages of maturation. Terminal maturation marked by Zeb2 expression includes the induction of S1P5, a gene essential to promote NK cell circulation within the bloodstream. Altogether our findings helped identify or characterize important checkpoints of NK cell function operating either in the nucleus to regulate the genetic program, or in the cell cytoplasm to regulate the metabolic capacity or trafficking properties. In the long term, this fundamental knowledge may help designing more efficient immune therapies based on the stimulation of NK cell function in patients with cancer or chronic infections.