EXPRESSION OF HLA-C MOLECULES CONFERS TARGET-CELL RESISTANCE TO SOME NONMAJOR HISTOCOMPATIBILITY COMPLEX-RESTRICTED T-CELLS IN A MANNER ANALOGOUS TO ALLOSPECIFIC NATURAL-KILLER-CELLS
EXPRESSION OF HLA-C MOLECULES CONFERS TARGET-CELL RESISTANCE TO SOME NONMAJOR HISTOCOMPATIBILITY COMPLEX-RESTRICTED T-CELLS IN A MANNER ANALOGOUS TO ALLOSPECIFIC NATURAL-KILLER-CELLS
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DOI：
10.1084/jem.182.4.1005
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发表时间：
1995-10-01
影响因子：
15.3
通讯作者：
SCHENDEL, DJ
中科院分区：
文献类型：
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作者：
FALK, CS;STEINLE, A;SCHENDEL, DJ
最近已表明特定的人类白细胞抗原（HLA）分子可使靶细胞对某些CD3（-）自然杀伤（NK）细胞的裂解产生抗性。对于某些NK克隆，抗性由与特定HLA - C等位基因相关的两种特异性（NK1和NK2）所决定：一般而言，表达Cw1、Cw3、Cw7或Cw8的靶细胞对NK1敏感但对NK2克隆有抗性，而表达Cw2、Cw4、Cw5或Cw6的靶细胞对NK2敏感且对NK1细胞有抗性。这两组HLA - C等位基因通过α1螺旋区的二态性加以区分，该二态性位于氨基酸位置77和80。在本报告中，我们表明，当针对一组同种异体淋巴母细胞样细胞系（LCL）以及各种HLA - B和 - C转染细胞系进行测试时，来自同一供体的高度富集的CD3（＋）/CD56（－）细胞毒性T细胞亚系和CD3（－）/CD56（＋）NK亚系具有相同的细胞溶解特异性。同种异体细胞的裂解模式似乎与两种效应细胞的NK2特异性相关：表达HLA - Cw2、Cw4、Cw5或Cw6等位基因的LCL被裂解，而表达HLA - Cw1、Cw3或Cw7分子的LCL具有抗性。通过转染Cw*0702基因可使敏感靶细胞获得抗性，而Cw*0602基因的表达则不提供保护。在由无关供体的外周血淋巴细胞产生的多克隆T细胞系中也发现了类似的HLA - C介导的抗性模式。因此，诱导对特定NK细胞产生抗性的主要组织相容性复合体（MHC）分子也调节了靶细胞对这些非MHC限制性效应T细胞裂解的抗性。对于这两种效应细胞，与HLA - C分子的直接结合对于实现抑制是必要的，因为用针对I类分子的单克隆抗体（mAb）预孵育会破坏对表达HLA - Cw7的靶细胞裂解的保护作用。针对CD3和CD8分子的单克隆抗体对NK样T细胞的裂解或抑制没有影响。与特定肽形成MHC复合物似乎并非赋予抗性所必需的，因为一个具有缺陷性肽转运体基因（TAP基因）的细胞系，当转染适当的HLA - C等位基因时，与具有正常TAP功能的HLA - C转染细胞系一样对裂解具有抗性。这些结果表明，HLA - C分子可能以类似于先前针对特定NK细胞所描述的方式向一些非MHC限制性T细胞传递负调节信号。
Specific HLA molecules have recently been shown to confer target cell resistance to lysis by some CD3(-) natural killer (NK) cells. For certain NK clones, resistance is governed by two specificities (NK1 and NK2) that are associated with particular HLA-C alleles: in general, target cells expressing Cw1, Cw3, Cw7, or Cw8 are susceptible to NK1 but resistant to NK2 clones, whereas target cells expressing Cw2, Cw4, Cw5, or Cw6 are susceptible to NK2 and resistant to NK1 cells. These two clusters of HLA-C alleles are distinguished by a dimorphism in the alpha 1 helical region, localized at amino acid positions 77 and 80. In this report, we show that highly enriched CD3(+)/CD56(-) cytotoxic T cell sublines and CD3(-)/CD56(+) NK sublines derived from the same donor have identical cytolytic specificities when tested against a panel of allegeneic LCL and various HLA-B and -C transfectant cell lines. The lysis pattern of the allogeneic cells appeared to be related to the NK2 specificity for both effector cells: LCL expressing HLA-Cw2, Cw4, Cw5, or CW6 alleles were lysed, while LCL expressing HLA-Cw1, Cw3, or Cw7 molecules were resistant. Resistance to lysis could be conferred to susceptible target cells by transfection with a Cw*0702 gene, while expression of a Cw*0602 gene did not provide protection. Similar patterns of HLA-C-mediated resistance were also found with mia polyclonal T cell lines generated from the peripheral blood lymphocytes of unrelated donors. Thus, major histocompatibility complex (MHC) molecules that induced resistance to particular NK cells also regulated target cell resistance to lysis by these non-MHC-restricted effector T cells. For both types of effector cells, direct binding to HLA-C molecules was necessary to achieve inhibition since preincubation with mAb specific for class I molecules destroyed the protection from lysis of HLA-Cw7 expressing target cells. mAbs specific for CD3 and CDS molecules had no influence on lysis or inhibition of the NK-like T cells. Formation of MHC complexes with particular peptides did not appear to be essential to confer resistance, since a cell line with defective peptide transporter genes (TAP genes), when transfected with an appropriate HLA-C allele, was as resistant to lysis as HLA-C transfectant lines with normal TAP function. These results suggest that HLA-C molecules may deliver negative regulatory signals to some non-MHC-restricted T cells in a manner similar to that described previously for particular NK cells.