NK cells are hematopoietic cells with the ability to kill a variety of tumors and to secrete immunoregulatory molecules with diverse effects over other hematopoietic lineages. Physiologically, they have been implicated in the clearance of intracellular pathogens, in the surveillance and destruction of newly developed tumors, and are the main effectors responsible for the rejection of bone marrow grafts. In addition, they have the potential to be utilized as vectors carrying different biological functions in adoptive immunotherapy protocols. NK cells are derived form bone marrow progenitors, through a probable common lymphoid progenitor. Phenotypically, they express on their surface a variety of molecules present in other hematopoietic lineages, as cell as NK lineage restricted markers. In addition it seems to be a defined distribution in the expression of markers in NK cells isolated from different tissues. The implications of this heterogeneity has not been studied extensively, in part by the lack of information on committed progenitors, by the low numbers of NK cells compared with the other lymphoid cells, and by the inability to generate and maintain clonal populations of NK cells in culture. The understanding of the development, heterogeneity and function of this compartment is important if we would like to design protocols aimed to modulate or alter NK cell functions in order to obtain better protection against pathogens, diminished reactivities against allogeneic hematopoietic grafts, and better immunotherapeutic vectors. The present application proposes to study the heterogeneity of the murine NK cell compartment from a developmental as well as form a functional prospective. Three main aims are considered: 1. To isolate and characterize NK cell committed progenitors from adult bone marrow. 2. To define the phenotype and functional heterogeneity of the NK cell compartment. 3. To establish methods to grow and propagate clonal cell lines of murine NK cells.
