Requirement for membrane lymphotoxin in natural killer cell development
Requirement for membrane lymphotoxin in natural killer cell development
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DOI：
10.1073/pnas.96.11.6336
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发表时间：
1999-05-25
影响因子：
11.1
通讯作者：
Fu, YX
中科院分区：
文献类型：
--
作者：
Iizuka, K;Chaplin, DD;Fu, YX
自然杀伤（NK）细胞的发育被认为取决于NK祖细胞和骨髓（BM）微环境之间的相互作用;然而，对所涉及的分子信号知之甚少。在这里，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。LT α（-/-）小鼠显示脾和BM NK和NWT细胞数量显著减少，NK和NWT细胞功能显著受损。缺乏肿瘤坏死因子受体（TNFR）-I或TNFR-II的小鼠具有正常数量的NK和NK/T细胞，这意味着这些细胞类型的发育不需要TNFR或可溶性LT α（3）。LT α（-/-）和轻度型小鼠之间的相互BM转移表明，膜LT表达NK细胞前体和LT反应性抗辐射基质细胞之间的密切相互作用是NK细胞发育所必需的。当LT缺陷型BM细胞与IL-15孵育时，形成NK细胞。此外，LT缺陷型BM细胞在活化后产生IL-15。因此，膜LT似乎为NK细胞发育递送信号，该信号独立于IL-15或在IL-15途径的上游。这些结果揭示了膜LT在NK和NK/T细胞发育中的新功能。它们还支持一种细胞和分子机制，通过这种机制，NK细胞前体本身通过膜配体传递必要的信号，诱导微环境以促进NK细胞和NK/T细胞的进一步发育。
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. LT alpha(-/-) mice show marked reduction in splenic and BM NK and NWT cell numbers and dramatically impaired NK and NWT 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 LT alpha(3) is required for development of these cell types. Reciprocal BM transfers between LT alpha(-/-) and mild-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.