The transmembrane sequence of human histocompatibility leukocyte antigen (HLA)-C as a determinant in inhibition of a subset of natural killer cells
The transmembrane sequence of human histocompatibility leukocyte antigen (HLA)-C as a determinant in inhibition of a subset of natural killer cells
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DOI：
10.1084/jem.189.8.1265
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发表时间：
1999-04-19
影响因子：
15.3
通讯作者：
Strominger, JL
中科院分区：
文献类型：
--
作者：
Davis, DM;Mandelboim, O;Strominger, JL
与I类主要组织相容性复合体蛋白的细胞外结构域的分子相互作用是免疫识别的主要决定因素，已经在物理和生物化学方面进行了广泛的研究。然而，尽管每个I类主要组织相容性复合体基因座内的独特功能严格保守，但这些蛋白质的跨膜或胞质氨基酸序列上尚未放置免疫功能。在这里，我们报告，溶解的一个子集的自然杀伤（NK）细胞的抑制靶细胞表达的人类组织相容性白细胞抗原（HLA）-Cw 6或-Cw 7的不抑制嵌合蛋白的表达组成的细胞外结构域的HLA-C和COOH末端部分的HLA-G。使用表达多种HLA-Cw 6突变体的转染子的测定鉴定了跨膜序列，特别是位置309处的半胱氨酸对于抑制68%（25/37）的NK细胞系和23%（33/145）的测试NK克隆是必需的。此外，发现这些被HLA-Cw 6的靶细胞表达抑制并依赖于跨膜序列的NK克隆不表达或仅微弱表达EB 6/HP 3E 4阳性的NK抑制性受体（NKIR 1）。此外，使用单克隆抗体阻断的测定表明，NKIR 1或CD 94以外的NK受体负责依赖于HLA-Cw 6的跨膜序列的识别。
Molecular interactions with the extracellular domains of class I major histocompatibility complex proteins are major determinants of immune recognition that have been extensively studied both physically and biochemically. However, no immunological function has yet been placed on the transmembrane or cytoplasmic amino acid sequences of these proteins despite strict conservation of unique features within each class I major histocompatibility complex locus. Here we report that lysis by a subset of natural killer (NK) cells inhibited by target cell expression of human histocompatibility leukocyte antigen (HLA)-Cw6 or -Cw7 was not inhibited by expression of chimeric proteins consisting of the extracellular domains of HLA-C and the COOH-tenninal portion of HLA-G. Assays using transfectants expressing a variety of HLA-Cw6 mutants identified the transmembrane sequence and, in particular, cysteine at position 309 as necessary for inhibition of 68% (25/37) of NK cell lines and 23% (33/145) of NK clones tested. Moreover, these NK clones inhibited by target cell expression of HLA-Cw6 and dependent upon the transmembrane sequence were found not to express or to only dimly express NK inhibitory receptors (NKIR1) that are EB6/HP3E4-positive. Furthermore, assays using monoclonal antibody blocking suggest that an NK receptor other than NKIR1 or CD94 is responsible for recognition dependent upon the transmembrane sequence of HLA-Cw6.