Salcedo M, Andersson M, Lemieux S, Van Kaer L, Chambers B J, Ljunggren H G
Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden.
Eur J Immunol. 1998 Apr;28(4):1315-21. doi: 10.1002/(SICI)1521-4141(199804)28:04<1315::AID-IMMU1315>3.0.CO;2-2.
TAP1-/-, beta2-microglobulin (beta2m)-/- and TAP1/beta2m-/- mice all express low but quantitatively different levels of MHC class I molecules. Using these mice, we have addressed questions relating to the fine tuning of natural killer (NK) cell specificity and maintenance of self tolerance in the NK cell system. NK cells from B6 wild-type mice killed target cells from TAP1-/-, beta2m-/- and TAP1/beta2m-/- mice in vivo and rejected bone marrow grafts from the same mice in vivo at equivalent levels. NK cells from TAP1-/-, beta2m-/- mice did not kill target cells or reject bone marrow grafts from TAP1/beta2m-/- mice. NK cells in all MHC class I-deficient mice were tolerant to autologous MHC class I-deficient cells, as revealed by in vitro cytotoxicity assays using NK cell effectors activated with the interferon-inducing agent Tilorone, or by in vivo bone marrow graft experiments. However, the self-tolerant state of MHC class I-deficient NK cells was broken by in vitro stimulation with IL-2 for 4 days. Under these conditions, NK cells from the MHC class I-deficient mice killed autologous MHC class I-deficient cells while MHC class I-positive targets were spared. The C-type lectin inhibitory receptor Ly49C has a specificity for H-2Kb and is expressed on a subset of NK1.1+ cells in B6 mice. Wild-type and all MHC class I-deficient mice had similar numbers of Ly49C-positive NK1.1+ cells. However, Ly49C expression was markedly down-regulated on NK1.1+ cells from B6 mice, as compared to TAP1-/-, beta2m-/- and TAP1/beta2m-/- mice. In vitro stimulation of NK cells with IL-2 for 4 days did not significantly change this pattern. The present results are discussed in relation to the role of MHC class I molecules and Ly49 receptors in shaping the NK cell repertoire and raise new questions about maintenance of self tolerance in the NK cell system.
TAP1基因敲除小鼠、β2微球蛋白（β2m）基因敲除小鼠以及TAP1/β2m双基因敲除小鼠均表达低水平但数量不同的MHC I类分子。利用这些小鼠，我们探讨了与自然杀伤（NK）细胞特异性的精细调节以及NK细胞系统中自身耐受性维持相关的问题。B6野生型小鼠的NK细胞在体内能杀伤TAP1基因敲除小鼠、β2m基因敲除小鼠以及TAP1/β2m双基因敲除小鼠的靶细胞，并且在体内以相同水平排斥来自相同小鼠的骨髓移植。TAP1基因敲除小鼠、β2m基因敲除小鼠的NK细胞不能杀伤TAP1/β2m双基因敲除小鼠的靶细胞，也不能排斥其骨髓移植。通过使用经干扰素诱导剂替洛隆激活的NK细胞效应物进行体外细胞毒性试验，或者通过体内骨髓移植实验发现，所有MHC I类缺陷小鼠中的NK细胞对自身MHC I类缺陷细胞具有耐受性。然而，MHC I类缺陷NK细胞的自身耐受状态在体外经白细胞介素-2刺激4天后被打破。在这些条件下，MHC I类缺陷小鼠的NK细胞能杀伤自身MHC I类缺陷细胞，而MHC I类阳性靶细胞则得以幸免。C型凝集素抑制性受体Ly49C对H-2Kb具有特异性，在B6小鼠的一部分NK1.1+细胞上表达。野生型小鼠和所有MHC I类缺陷小鼠中Ly49C阳性NK1.1+细胞的数量相似。然而，与TAP1基因敲除小鼠、β2m基因敲除小鼠以及TAP1/β2m双基因敲除小鼠相比，B6小鼠NK1.1+细胞上的Ly49C表达明显下调。用白细胞介素-2体外刺激NK细胞4天并未显著改变这种模式。本文结合MHC I类分子和Ly49受体在塑造NK细胞库中的作用对目前的结果进行了讨论，并提出了关于NK细胞系统中自身耐受性维持的新问题。
