FETAL MOUSE NK CELL CLONES ARE DEFICIENT IN LY49 EXPRESSION, SHARE A COMMON BROAD LYTIC SPECIFICITY, AND UNDERGO CONTINUOUS AND EXTENSIVE DIVERSIFICATION IN-VITRO

NK cells obtained by exposing mouse fetal thymocytes to appropriate co mbinations of IL-4, IL-2, and PMA are phenotypically indistinguishable from cultured adult splenic NK cells,vith the exception that they gen erally lack measurable expression of all of the inhibitory Ly49 molecu les that can currently be detected with Abs (Ly49A, -C, -G, and -I) an d of the activating molecule Ly49D, Despite this deficiency, fetal NK cells have a similar specificity to Ly49-expressing adult splenic NK c ells, Individual fetal NK cell clones display an essentially invariant and broad specificity similar to that of polyclonal populations of fe tal or adult NK cells, although significant differences in the fine sp ecificity of clones can occasionally be detected, Most remarkably, clo ned fetal NK cell lines display heterogeneous expression of a restrict ed set of surface molecules that includes 10A7, Ly6C, 3C2, CD8, certai n isoforms of CD45, and also, occasionally, Ly49 molecules, This heter ogeneity is not related to the cell cycle or activation status of the cells, and micromanipulation recloning demonstrates unambiguously that it is not due to a lack of a single cell origin, Diversity is generat ed rapidly and the capacity for diversification appears to persist ind efinitely in vitro, The expression of individual variable Ags is indep endent and stochastic, resulting in fetal NK ''clones'' being potentia lly composed of hundreds of phenotypically distinct cells, We hypothes ize that fetal NK cells behave as progenitor cells that are undergoing a process of rapid, extensive, and continuous diversification and tha t are individually capable of generating and regenerating a complex NK cell repertoire.