Zuo Jianmin, Willcox Carrie R, Mohammed Fiyaz, Davey Martin, Hunter Stuart, Khan Kabir, Antoun Ayman, Katakia Poonam, Croudace Joanne, Inman Charlotte, Parry Helen, Briggs David, Malladi Ram, Willcox Benjamin E, Moss Paul
Cancer Immunology and Immunotherapy Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TT, UK.
Department of Haematology, University Hospital Birmingham, Birmingham B15 2TH, UK.
Sci Signal. 2017 May 30;10(481):eaai8904. doi: 10.1126/scisignal.aai8904.
NKG2D (natural killer group 2, member D) is an activating receptor found on the surface of immune cells, including natural killer (NK) cells, which regulates innate and adaptive immunity through recognition of the stress-induced ligands ULBP1 (UL16 binding protein 1) to ULBP6 and MICA/B. Similar to class I human leukocyte antigen (HLA), these NKG2D ligands have a major histocompatibility complex-like fold and exhibit pronounced polymorphism, which influences human disease susceptibility. However, whereas class I HLA polymorphisms occur predominantly in the α1α2 groove and affect antigen binding, the effects of most NKG2D ligand polymorphisms are unclear. We studied the molecular and functional consequences of the two major alleles of , the most polymorphic gene, which are associated with autoimmunity and relapse after stem cell transplantation. Surface plasmon resonance and crystallography studies revealed that the arginine-to-leucine polymorphism within ULBP0602 affected the NKG2D-ULBP6 interaction by generating an energetic hotspot. This resulted in an NKG2D-ULBP0602 affinity of 15.5 nM, which is 10- to 1000-fold greater than the affinities of other ULBP-NKG2D interactions and limited NKG2D-mediated activation. In addition, soluble ULBP0602 exhibited high-affinity competitive binding for NKG2D and partially suppressed NKG2D-mediated activation of NK cells by other NKG2D ligands. These effects resulted in a decrease in a range of NKG2D-mediated effector functions. Our results reveal that polymorphisms affect the strength of human lymphocyte responses to cellular stress signals and may offer opportunities for therapeutic intervention.
NKG2D（自然杀伤细胞2族D成员）是一种在免疫细胞表面发现的激活受体，包括自然杀伤（NK）细胞，它通过识别应激诱导的配体ULBP1（UL16结合蛋白1）至ULBP6以及MICA/B来调节先天性和适应性免疫。与I类人类白细胞抗原（HLA）相似，这些NKG2D配体具有主要组织相容性复合体样折叠并表现出明显的多态性，这会影响人类疾病易感性。然而，虽然I类HLA多态性主要发生在α1α2凹槽中并影响抗原结合，但大多数NKG2D配体多态性的影响尚不清楚。我们研究了最具多态性的基因的两个主要等位基因的分子和功能后果，这两个等位基因与自身免疫和干细胞移植后的复发有关。表面等离子体共振和晶体学研究表明，ULBP0602内的精氨酸到亮氨酸多态性通过产生一个能量热点影响NKG2D-ULBP6相互作用。这导致NKG2D-ULBP0602的亲和力为15.5 nM，比其他ULBP-NKG2D相互作用的亲和力高10至1000倍，并限制了NKG2D介导的激活。此外，可溶性ULBP0602对NKG2D表现出高亲和力竞争性结合，并部分抑制其他NKG2D配体介导的NK细胞激活。这些效应导致一系列NKG2D介导的效应功能下降。我们的结果表明，基因多态性会影响人类淋巴细胞对细胞应激信号的反应强度，并可能为治疗干预提供机会。
