Regulation of NK1.1 expression during lineage commitment of progenitor thymocytes

We recently identified a stage in fetal ontogeny (NK1.1(+)/CD117(+)) that d efines committed progenitors for T and NK lymphocytes. These cells are Foun d in the fetal thymus as early as day 13 of gestation, but are absent in th e fetal liver. Nonetheless, multipotent precursors derived from both the fe tal thymus and fetal liver are capable of rapidly differentiating to the NK 1.1(+) stage upon transfer into fetal thymic organ culture (FTOC), This sug gests that expression of NK1.1 marks a thymus-induced lineage commitment ev ent, We now report that a subset of the most immature fetal thymocytes (NK1 .1(-)/CD117(+)) is capable of up-regulating NK1.1 expression spontaneously upon short-term in vitro culture. Interestingly, fetal liver-derived CD117( +) precursors remain NK1.1(-) upon similar culture. Spontaneous up-regulati on of NK1.1 surface expression is minimally affected by transcriptional blo ckade, mitogen-induced activation, or exposure of these cells to exogenous cytokines or stromal cells, These data suggest that induction of NK1.1 expr ession on cultured thymocytes may be predetermined by exposure to the thymi c microenvironment in vivo. Importantly, multipotent CD117(+) thymocytes su bdivided on the basis of NK1.1 expression after short-term in vitro culture show distinct precursor potential in lymphocyte Lineage reconstitution ass ays. This demonstrates that even the earliest precursor thymocyte populatio n, although phenotypically homogeneous, contains a functionally heterogeneo us subset of lineage-committed progenitors. These findings characterize a t hymus-induced pathway in the control of lymphocyte lineage commitment to th e T and NK cell fates.