NATURAL-KILLER-CELL DEVELOPMENT AND FUNCTION PRECEDE ALPHA-BETA-T-CELL DIFFERENTIATION IN MOUSE FETAL THYMIC ONTOGENY

Natural killer (NK) cells mediate MHC-unrestricted cytolysis of virus- infected cells and tumor cells, In the adult mouse, NK cells are bone marrow-derived lymphocytes that mature predominantly in extrathymic lo cations but have also been suggested to share a common intrathymic pro genitor with T lymphocytes. However, mature NK cells are thought to be absent in mouse fetal ontogeny, We report the existence of thymocytes with a mature NK cell phenotype (NK1.1(+)/CD117(-)) as early as day 1 3 of gestation, approximately 3 days before the appearance of CD4(+)/C D8(+) cells in T lymphocyte development. These mature fetal thymic NK cells express genes associated with NK cell effector function and, whe n freshly isolated, display MHC-unrestricted cytolytic activity in vit ro, Moreover, the capacity of fetal thymic NK cells for sustained grow th both in vitro and in vivo, in addition to their close phenotypic re semblance to early precursor thymocytes, confounds previous assessment s of NK lineage precursor function, Thus, mature NK cells may have bee n inadvertently included in previous attempts to identify multipotent and bipotent precursor thymocytes. These results provide the first evi dence of functional NK lymphocytes in mouse fetal ontogeny and demonst rate that NK cell maturation precedes alpha beta T cell development in the fetal thymus.