Signal via Lymphotoxin-βR on bone marrow stromal cells is required for an early checkpoint of NK cell development

NK cells play an important role in the immune system but the cellular and molecular requirements for their early development are poorly understood. Lymphotoxin-alpha (LT alpha)(-/-) and LT betaR(-/-) mice show a severe systemic reduction of NK cells, which provides an excellent model to study NK cell development. In this study, we show that the bone marrow (BM) or fetal liver cells from LT alpha (-/-) or LT betaR(-/-) mice efficiently develop into mature NK cells in the presence of stromal cells from wild-type mice but not from LT alpha (-/-) or LT betaR(-/-) mice. Direct activation of LT betaR-expressing BM stromal cells is shown to promote to early NK cell development in vitro. Furthermore, the blockade of the interaction between LT and LT betaR in adult wild-type mice by administration of LT betaR-Ig impairs the development of NK cells in vivo. Together, these results indicate that the signal via LT betaR on BM stromal cells by membrane LT is an important pathway for early NK cell development.