Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA.
J Immunol. 2013 May 1;190(9):4650-60. doi: 10.4049/jimmunol.1202120. Epub 2013 Apr 3.
NK cells are regulated by inhibiting and activating cell surface receptors. Most inhibitory receptors recognize MHC class I Ags and protect healthy cells from NK cell-mediated autoaggression. However, certain activating receptors, including the human activating killer cell Ig-like receptor (KIR) 2DS1, also recognize MHC class I. This fact raises the question of how NK cells expressing such activating receptors are tolerized to host tissues. We investigated whether the presence of HLA-C2, the cognate ligand for 2DS1, induces tolerance in 2DS1-expressing NK cells. Anti-HLA-C2 activity could be detected in vitro in some 2DS1 positive NK clones irrespective of the presence or absence of HLA-C2 ligand in the donor. The frequency of anti-HLA-C2 reactivity was high in donors homozygous for HLA-C1. Surprisingly, no significant difference was seen in the frequency of anti-HLA-C2 cytotoxicity in donors heterozygous for HLA-C2 and donors without HLA-C2 ligand. However, donors homozygous for HLA-C2, compared with all other donors, had significantly reduced frequency of anti-HLA-C2 reactive clones. The 2DS1 positive clones that express inhibitory KIR for self-HLA class I were commonly noncytotoxic, and anti-HLA-C2 cytotoxicity was nearly exclusively restricted to 2DS1 single positive clones lacking inhibitory KIR. 2DS1 single positive NK clones with anti-HLA-C2 reactivity were also present posttransplantation in HLA-C2 positive recipients of hematopoietic stem cell transplants from 2DS1 positive donors. These results demonstrate that many NK cells with anti-HLA-C2 reactivity are present in HLA-C1 homozygous and heterozygous donors with 2DS1. In contrast, 2DS1 positive clones from HLA-C2 homozygous donors are frequently tolerant to HLA-C2.
自然杀伤（NK）细胞受抑制性和激活型细胞表面受体的调控。大多数抑制性受体识别主要组织相容性复合体（MHC）I 类抗原，并保护健康细胞免受 NK 细胞介导的自身攻击。然而，某些激活型受体，包括人类激活杀伤细胞免疫球蛋白样受体（KIR）2DS1，也识别 MHC I 类。这一事实提出了一个问题，即表达此类激活受体的 NK 细胞如何耐受宿主组织。我们研究了表达 2DS1 的 NK 细胞中是否存在 HLA-C2（2DS1 的配体）会诱导其对自身产生耐受。在一些 2DS1 阳性 NK 克隆中，无论供体中是否存在 HLA-C2 配体，均可在体外检测到抗 HLA-C2 的活性。在 HLA-C1 纯合子供体中，抗 HLA-C2 反应性的频率较高。令人惊讶的是，在 HLA-C2 杂合子供体和没有 HLA-C2 配体的供体中，抗 HLA-C2 细胞毒性的频率没有显著差异。与所有其他供体相比，HLA-C2 纯合子供体的抗 HLA-C2 反应性克隆频率显著降低。表达针对自身 HLA I 类抑制性 KIR 的 2DS1 阳性克隆通常无细胞毒性，并且抗 HLA-C2 细胞毒性几乎完全局限于缺乏抑制性 KIR 的 2DS1 单阳性克隆。具有抗 HLA-C2 反应性的 2DS1 阳性 NK 克隆在 HLA-C2 阳性接受者中也存在于来自 2DS1 阳性供体的造血干细胞移植后。这些结果表明，在 HLA-C1 纯合子和杂合子供体中存在许多具有抗 HLA-C2 反应性的 NK 细胞，这些供体携带 2DS1。相比之下，来自 HLA-C2 纯合子供体的 2DS1 阳性克隆对 HLA-C2 通常具有耐受性。
