Lu Linrong, Ikizawa Koichi, Hu Dan, Werneck Miriam B F, Wucherpfennig Kai W, Cantor Harvey
Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Immunity. 2007 May;26(5):593-604. doi: 10.1016/j.immuni.2007.03.017.
The ability of natural-killer cells to regulate adaptive immunity is not well understood. Here we define an interaction between the class Ib major histocompatibility complex (MHC) molecule Qa-1-Qdm on activated T cells responsible for adaptive immunity and CD94-NKG2A inhibitory receptors expressed by natural-killer cells by using Qa-1-deficient and Qa-1 knockin mice containing a point mutation that selectively abolishes Qa-1-Qdm binding to CD94-NKG2A receptors. The Qa-1-NKG2A interaction protected activated CD4+ T cells from lysis by a subset of NKG2A+ NK cells and was essential for T cell expansion and development of immunologic memory. Antibody-dependent blockade of this Qa-1-NKG2A interaction resulted in potent NK-dependent elimination of activated autoreactive T cells and amelioration of experimental autoimmune encephalomyelitis. These findings extend the functional reach of the NK system to include regulation of adaptive T cell responses and suggest a new clinical strategy for elimination of antigen-activated T cells in the context of autoimmune disease and transplantation.
自然杀伤细胞调节适应性免疫的能力尚未得到充分了解。在这里，我们通过使用缺乏Qa-1的小鼠和含有选择性消除Qa-1-Qdm与CD94-NKG2A受体结合的点突变的Qa-1基因敲入小鼠，定义了负责适应性免疫的活化T细胞上的Ib类主要组织相容性复合体（MHC）分子Qa-1-Qdm与自然杀伤细胞表达的CD94-NKG2A抑制性受体之间的相互作用。Qa-1与NKG2A的相互作用保护活化的CD4+ T细胞不被一部分NKG2A+自然杀伤细胞裂解，并且对于T细胞扩增和免疫记忆的发展至关重要。对这种Qa-1-NKG2A相互作用的抗体依赖性阻断导致活化的自身反应性T细胞被自然杀伤细胞有效清除，并改善了实验性自身免疫性脑脊髓炎。这些发现扩展了自然杀伤细胞系统的功能范围，使其包括对适应性T细胞反应的调节，并提出了一种在自身免疫性疾病和移植背景下消除抗原活化T细胞的新临床策略。
