Trowsdale J, Barten R, Haude A, Stewart C A, Beck S, Wilson M J
Department of Pathology, University of Cambridge, UK.
Immunol Rev. 2001 Jun;181:20-38. doi: 10.1034/j.1600-065x.2001.1810102.x.
The two sets of inhibitory and activating natural killer (NK) receptor genes belong either to the Ig or to the C-type lectin superfamilies. Both are extensive and diverse, comprising genes of varying degrees of relatedness, indicative of a process of iterative duplication. We have constructed gene maps to help understand how and when NK receptor genes developed and the nature of their polymorphism. A cluster of over 15 C-type lectin genes, the natural killer complex is located on human chromosome 12p13.1, syntenic with a region in mouse that borders multiple Ly49 loci. The equivalent locus in man is occupied by a single pseudogene, LY49L. The immunoglobulin superfamily of loci, the leukocyte receptor complex (LRC), on chromosome 19q13.4, contains many polymorphic killer cell immunoglobulin-like receptor (KIR) genes as well as multiple related sequences. These include immunoglobulin-like transcript (ILT) (or leukocyte immunoglobulin-like receptor genes), leukocyte-associated inhibitory receptor genes (LAIR), NKp46, Fc alphaR and the platelet glycoprotein receptor VI locus, which encodes a collagen-binding molecule. KIRs are expressed mostly on NK cells and some T cells. The other LRC loci are more widely expressed. Further centromeric of the LRC are sets of additional loci with weak sequence similarity to the KIRs, including the extensive CD66(CEA) and Siglec families. The LRC-syntenic region in mice contains no orthologues of KIRs. Some of the KIR genes are highly polymorphic in terms of sequence as well as for presence/absence of genes on different haplotypes. Some anchor loci, such as KIR2DL4, are present on most haplotypes. A few ILT loci, such as ILT5 and ILT8, are polymorphic, but only ILT6 exhibits presence/absence variation. This knowledge of the genomic organisation of the extensive NK superfamilies underpins efforts to understand the functions of the encoded NK receptor molecules. It leads to the conclusion that the functional homology of human KIR and mouse Ly49 genes arose by convergent evolution. NK receptor immunogenetics has interesting parallels with the major histocompatibility complex (MHC) in which some of the polymorphic genes are ligands for NK molecules. There are hints of an ancient genetic relationship between NK receptor genes and MHC-paralogous regions on chromosomes 1, 9 and 19. The picture that emerges from both complexes is of eternal evolutionary restlessness, presumably in response to resistance to disease.
两组抑制性和激活性自然杀伤（NK）受体基因分别属于免疫球蛋白（Ig）超家族或C型凝集素超家族。这两个家族都很庞大且多样，包含不同程度相关性的基因，这表明存在一个反复复制的过程。我们构建了基因图谱，以帮助理解NK受体基因是如何以及何时发展的，以及它们多态性的本质。超过15个C型凝集素基因组成的一个簇，即自然杀伤复合体，位于人类染色体12p13.1上，与小鼠中一个与多个Ly49基因座相邻的区域同线。人类中的等效基因座被一个单一的假基因LY49L占据。位于染色体19q13.4上的白细胞受体复合体（LRC），即免疫球蛋白超家族基因座，包含许多多态性的杀伤细胞免疫球蛋白样受体（KIR）基因以及多个相关序列。这些包括免疫球蛋白样转录本（ILT）（或白细胞免疫球蛋白样受体基因）、白细胞相关抑制性受体基因（LAIR）、NKp46、FcαR以及血小板糖蛋白受体VI基因座，后者编码一种胶原结合分子。KIR主要在NK细胞和一些T细胞上表达。LRC的其他基因座表达更为广泛。在LRC更靠近着丝粒的位置还有一些与KIR序列相似性较弱的额外基因座，包括广泛的CD66（癌胚抗原）和唾液酸结合凝集素家族。小鼠中的LRC同线区域不包含KIR的直系同源物。一些KIR基因在序列以及不同单倍型上基因的存在/缺失方面具有高度多态性。一些锚定基因座，如KIR2DL4，存在于大多数单倍型上。一些ILT基因座，如ILT5和ILT8，是多态的，但只有ILT6表现出存在/缺失变异。对庞大的NK超家族基因组组织的这种了解为理解编码的NK受体分子的功能提供了基础。由此得出结论，人类KIR和小鼠Ly49基因的功能同源性是通过趋同进化产生的。NK受体免疫遗传学与主要组织相容性复合体（MHC）有有趣的相似之处，其中一些多态性基因是NK分子的配体。有迹象表明NK受体基因与染色体1、9和19上的MHC旁系同源区域之间存在古老的遗传关系。从这两个复合体中呈现出的图景是永恒的进化动荡，大概是为了应对疾病抗性。
