Kim Sungjin, Poursine-Laurent Jennifer, Truscott Steven M, Lybarger Lonnie, Song Yun-Jeong, Yang Liping, French Anthony R, Sunwoo John B, Lemieux Suzanne, Hansen Ted H, Yokoyama Wayne M
Howard Hughes Medical Institute, Rheumatology Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Nature. 2005 Aug 4;436(7051):709-13. doi: 10.1038/nature03847.
Self versus non-self discrimination is a central theme in biology from plants to vertebrates, and is particularly relevant for lymphocytes that express receptors capable of recognizing self-tissues and foreign invaders. Comprising the third largest lymphocyte population, natural killer (NK) cells recognize and kill cellular targets and produce pro-inflammatory cytokines. These potentially self-destructive effector functions can be controlled by inhibitory receptors for the polymorphic major histocompatibility complex (MHC) class I molecules that are ubiquitously expressed on target cells. However, inhibitory receptors are not uniformly expressed on NK cells, and are germline-encoded by a set of polymorphic genes that segregate independently from MHC genes. Therefore, how NK-cell self-tolerance arises in vivo is poorly understood. Here we demonstrate that NK cells acquire functional competence through 'licensing' by self-MHC molecules. Licensing involves a positive role for MHC-specific inhibitory receptors and requires the cytoplasmic inhibitory motif originally identified in effector responses. This process results in two types of self-tolerant NK cells--licensed or unlicensed--and may provide new insights for exploiting NK cells in immunotherapy. This self-tolerance mechanism may be more broadly applicable within the vertebrate immune system because related germline-encoded inhibitory receptors are widely expressed on other immune cells.
自我与非自我识别是从植物到脊椎动物生物学中的一个核心主题，对于表达能够识别自身组织和外来入侵者的受体的淋巴细胞尤为重要。自然杀伤（NK）细胞构成第三大淋巴细胞群体，可识别并杀死细胞靶标并产生促炎细胞因子。这些潜在的自我毁灭效应功能可由靶细胞上普遍表达的多态性主要组织相容性复合体（MHC）I类分子的抑制性受体控制。然而，抑制性受体在NK细胞上并非均匀表达，而是由一组与MHC基因独立分离的多态性基因种系编码。因此，NK细胞在体内如何产生自我耐受性尚不清楚。在这里，我们证明NK细胞通过自身MHC分子的“许可”获得功能能力。许可涉及MHC特异性抑制性受体的积极作用，并且需要最初在效应反应中鉴定的细胞质抑制基序。这个过程产生了两种类型的自我耐受NK细胞——许可的或未许可的——并且可能为在免疫治疗中利用NK细胞提供新的见解。这种自我耐受机制可能在脊椎动物免疫系统中更广泛适用，因为相关的种系编码抑制性受体在其他免疫细胞上广泛表达。
