DIFFERENTIAL-EFFECTS OF INTERLEUKIN-15 AND INTERLEUKIN-2 ON DIFFERENTIATION OF BIPOTENTIAL T NATURAL KILLER PROGENITOR CELLS/

Bipotential T/natural killer (NK) progenitor cells are destined to dif ferentiate mainly into T cell receptor (TCR)alpha beta and TCR gamma d elta cells in a thymic microenvironment, whereas extrathymically they selectively develop into NK cells, The exact environmental conditions that are required for differentiation into these three leukocyte popul ations are largely unknown. In this report, we have investigated and c ompared the effect of interleukin (IL)-15 and IL-2 in this process. Th e IL-15 receptor is composed of the gamma and beta chains of the IL-2 receptor (IL-2R gamma and IL-2R beta) and of a specific alpha chain (I L-15R alpha). Here, it is shown that IL-15 mRNA is mainly expressed in thymic epithelial stromal cells, whereas IL-2 mRNA is exclusively exp ressed in thymocytes. IL-2R beta-expressing cells were present in the fetal thymus with a CD25(-)CD44(+)Fc gamma R(+)HSA(-/low)TCR(-) phenot ype, which is characteristic of progenitor cells, These cells also exp ressed IL-15R alpha messenger RNA. Sorted IL-2R beta(+)TCR(-) cells di fferentiated into TCR alpha beta and TCR gamma delta cells after trans fer to alymphoid thymic lobes, whereas culture of the same sorted cell s in cell suspension in the presence of IL-15 resulted in the generati on of functional NK cells. This shows that IL-2R beta(+)TCR(-) cells o f the fetal thymus contain bipotential T/NK progenitors. Addition of l ow concentrations of IL-15 to fetal thymic organ culture (FTOC) result ed in an increase of all T cell subpopulations. The largest expansion occurred in the TCR gamma delta compartment. In contrast, low concentr ations of IL-2 did not result in a higher total cell number and did no t induce outgrowth of TCR gamma delta cells. High concentrations of IL -15 blocked TCR alpha beta development and shifted differentiation tow ards NK cells. Differentiation towards TCR gamma delta cells still pro ceeded. High concentrations of IL-2 similarly induced development into NK cells, but the cell number was fourfold lower than in IL-15 cultur es. Importantly, blocking of IL-2R alpha in IL-2-treated FTOC resulted in a drastic increase ill cell number, indicating that IL-2R alpha ne gatively regulates cell expansion. Collectively, these experiments pro vide direct evidence that IL-15 and IL-2 differentially affect the dif ferentiation of bipotential T/NK progenitors.