Signal via Lymphotoxin-beta R on bone marrow stromal cells is required foran early checkpoint of NK cell development

NK cells play an important role in the immune system but the cellular and m olecular requirements for their early development are poorly understood. Ly mphotoxin-alpha (LT alpha)(-/-) and LT betaR(-/-) mice show a severe system ic reduction of NK cells, which provides an excellent model to study NK cel l development. In this study, we show that the bone marrow (BM) or fetal li ver cells from LT alpha (-/-) or LT betaR(-/-) mice efficiently develop int o 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 beta R-expressing BM stromal cells is shown to promote to early NK cell developm ent in vitro. Furthermore, the blockade of the interaction between LT and L T betaR in adult wild-type mice by administration of LT betaR-Ig impairs th e development of NK cells in vivo. Together, these results indicate that th e signal via LT betaR on BM stromal cells by membrane LT is an important pa thway for early NK cell development.