Effects of interleukin-15 on human CD3(-)CD117(+)CD56(-)OX40L(+) cell differentiation

Lymphoid tissue inducer (LTi) cells are essential for secondary lymphoid tissue development, and recently identified human LTi cells are closely related to natural killer (NK) cells. In this study, we investigate whether human CD3(-)CD117(+)CD56(-) cells that include LTi and immature NK cells respond to interleukin (IL)-15, which is an NK cell growth factor. In the presence of IL-15, CD3(-)CD117(+)CD56(-) cells proliferate and downregulate the expression of OX40L and mRNA for IL-22, lymphotoxin-alpha, and aryl hydrocarbon receptor, but not Id2. To examine whether CD(-)CD117(+)CD56(-) cells differentiate into CD3(-)CD117(+)CD56(+) NK cells by IL-15, we sorted CD3(-)CD117(+)CD56(-)OX40L(+) cells and cultured with IL-15 for 7 days. Approximately 75% of the cells differentiated into imterferon-gamma-expressing CD56(+) cells and approximately 25% of the cells did not. In addition, the latter population expressed LTi markers, including lymphotoxin-alpha and retinoid-related orphan receptor-gamma (RORC). These results show that approximately 25% of CD3(-)CD117(+)CD56(-)OX40L(+) cells are LTi cells and do not differentiate into CD56(+) NK cells by IL-15.