Iizuka K, Chaplin D D, Wang Y, Wu Q, Pegg L E, Yokoyama W M, Fu Y X
Departments of Internal Medicine and Pathology, Howard Hughes Medical Institute, and Center for Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Proc Natl Acad Sci U S A. 1999 May 25;96(11):6336-40. doi: 10.1073/pnas.96.11.6336.
Development of natural killer (NK) cells is thought to depend on interactions between NK progenitors and the bone marrow (BM) microenvironment; however, little is known about the molecular signals involved. Here we show that lymphotoxin (LT) provides an important signal for the development of both NK cells and NK/T cells. LTalpha-/- mice show marked reduction in splenic and BM NK and NK/T cell numbers and dramatically impaired NK and NK/T cell function. Mice deficient in either tumor necrosis factor receptor (TNFR)-I or TNFR-II have normal numbers of NK and NK/T cells, implying that neither of the TNFRs nor soluble LTalpha3 is required for development of these cell types. Reciprocal BM transfers between LTalpha-/- and wild-type mice suggest that close interactions between membrane LT-expressing NK cell precursors and LT-responsive radioresistant stromal cells are necessary for NK cell development. When LT-deficient BM cells are incubated with IL-15, NK cells are formed. In addition, LT-deficient BM cells produce IL-15 after activation. Thus, membrane LT appears to deliver a signal for NK cell development that is either independent of IL-15 or upstream in the IL-15 pathway. These results reveal a novel function for membrane LT in NK and NK/T cell development. 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.
自然杀伤（NK）细胞的发育被认为依赖于NK祖细胞与骨髓（BM）微环境之间的相互作用；然而，对于其中涉及的分子信号却知之甚少。在此我们表明，淋巴毒素（LT）为NK细胞和NK/T细胞的发育提供了重要信号。LTα-/-小鼠脾脏和骨髓中的NK细胞及NK/T细胞数量显著减少，且NK细胞和NK/T细胞功能严重受损。肿瘤坏死因子受体（TNFR）-I或TNFR-II缺陷的小鼠NK细胞和NK/T细胞数量正常，这意味着这些细胞类型的发育不需要TNFRs或可溶性LTα3。LTα-/-小鼠与野生型小鼠之间的相互骨髓移植表明，表达膜LT的NK细胞前体与对LT有反应的抗辐射基质细胞之间的紧密相互作用对于NK细胞发育是必需的。当LT缺陷的骨髓细胞与IL-15一起培养时，会形成NK细胞。此外，LT缺陷的骨髓细胞激活后会产生IL-15。因此，膜LT似乎传递了一个NK细胞发育信号，该信号要么独立于IL-15，要么在IL-15信号通路的上游。这些结果揭示了膜LT在NK细胞和NK/T细胞发育中的新功能。它们还支持了一种细胞和分子机制，即NK细胞前体自身通过膜配体传递必要信号，诱导微环境促进NK细胞和NK/T细胞的进一步发育。
