SHIP Influences Signals from CD48 and MHC Class I Ligands That Regulate NK Cell Homeostasis, Effector Function, and Repertoire Formation
SHIP Influences Signals from CD48 and MHC Class I Ligands That Regulate NK Cell Homeostasis, Effector Function, and Repertoire Formation
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DOI：
10.4049/jimmunol.0901862
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发表时间：
2010-05-01
影响因子：
4.4
通讯作者：
Kerr, William G.
中科院分区：
文献类型：
--
作者：
Fortenbery, Nicole R.;Paraiso, Kim H. T.;Kerr, William G.
之前，我们证明2B 4是SHIP缺陷型NK细胞中的一种主要抑制性受体，可以阻止复杂靶点的有效细胞溶解。我们在这项研究中表明，2B 4缺陷恢复稳态控制和细胞溶解功能的SHIP缺陷的NK细胞。然而，2B 4（-/-）SHIP（-/-）NK细胞仍然表现出对其NK受体库的严重破坏，并且在通过几种NK活化受体（包括NKp 46、NK.1.1和NKG 2D）诱导IFN-γ方面受到损害。此外，我们发现2B 4（-/-）NK细胞具有广泛破坏的库，包括NKp 46（+）NK细胞的超常频率。因此，在NKp 46参与后，IFN-γ在更高百分比的2B 4（-/-）NK细胞上被诱导。我们还发现SHIP和2B 4都需要防止Ly 49 B的表达，Ly 49 B是一种髓系MHC I类受体，通常不被NK谱系表达。最后，当SHIP缺陷型NK细胞处于H-2（d）背景下时，它们表现出超常水平的Ly 49 A，并具有针对MHC匹配的肿瘤靶标的正常细胞溶解功能和增强的MHC不匹配的肿瘤靶标的细胞溶解。然而，尽管细胞溶解功能正常或升高，但H2 d SHIP-/- NK细胞表现出与其H2 b（+）或2B 4（-/-）对应物一样的IFN-γ诱导差，表明在关键NK活化受体下游诱导IFN-γ中对SHIP的一致需求。这些发现揭示了SHIP、2B 4和MHC在调节NK细胞谱系的稳态、效应器功能和库形成中的复杂相互作用。免疫学杂志，2010，184：5065-5074。
Previously, we showed that 2B4 is a dominant inhibitory receptor in SHIP-deficient NK cells that prevents efficient cytolysis of complex targets. We show in this study that 2B4 deficiency restores homeostatic control and cytolytic function to SHIP-deficient NK cells. However, 2B4(-/-)SHIP(-/-) NK cells still exhibit a profound disruption of their NK receptor repertoire and are compromised for induction of IFN-gamma by several NK-activating receptors, including NKp46, NK.1.1, and NKG2D. In addition, we find that 2B4(-/-) NK cells have an extensively disrupted repertoire, including a supernormal frequency of NKp46(+) NK cells. Consequently IFN-gamma is induced on a much higher percentage of 2B4(-/-) NK cells following engagement of NKp46. We also find that both SHIP and 2B4 are required to prevent expression of Ly49B, a myeloid lineage MHC class I receptor not normally expressed by the NK lineage. Finally, when SHIP-deficient NK cells are on an H-2(d) background, they exhibit supernormal levels of Ly49A and possess normal cytolytic function against MHC-matched tumor targets and enhanced cytolysis of MHC mismatched tumor targets. However, despite normal or elevated cytolytic function, H2d SHIP-/- NK cells exhibit poor induction of IFN-gamma like their H2b(+) or 2B4(-/-) counterparts, demonstrating a uniform requirement for SHIP in induction of IFN-gamma downstream of key NK activating receptors. These findings reveal a complex interplay of SHIP, 2B4, and MHC in the regulation of homeostasis, effector function, and repertoire formation in the NK cell lineage. The Journal of Immunology, 2010, 184: 5065-5074.