Requirement for membrane lymphotoxin in natural killer cell development

Development of natural killer (NK) cells is thought to depend on interactio ns between NK progenitors and the bone marrow (BM) microenvironment; howeve r, little is known about the molecular signals involved. Here we show that lymphotoxin (LT) provides an important signal for the development of both N K cells and NK/T cells. LT alpha(-/-) mice show marked reduction in splenic and BM NK and NWT cell numbers and dramatically impaired NK and NWT cell f unction. Mice deficient in either tumor necrosis factor receptor (TNFR)-I o r TNFR-II have normal numbers of NK and NK/T cells, implying that neither o f the TNFRs nor soluble LT alpha(3) is required for development of these ce ll types. Reciprocal BM transfers between LT alpha(-/-) and mild-type mice suggest that close interactions between membrane LT-expressing NK cell prec ursors and LT-responsive radioresistant stromal cells are necessary for NK cell development. When LT-deficient BM cells are incubated with IL-15, NK c ells are formed. In addition, LT deficient BM cells produce IL-15 after act ivation. Thus, membrane LT appears to deliver a signal for NK cell developm ent that is either independent of IL-15 or upstream in the IL-15 pathway, T hese results reveal a novel function for membrane LT in NK and NK/T cell de velopment. They also support a cellular and molecular mechanism by which NK cell precursors themselves deliver essential signals, through the membrane ligand, that induce the microenvironment to promote further NK cell and NK /T cell development.