Moesta Achim K, Abi-Rached Laurent, Norman Paul J, Parham Peter
Department of Structural Biology, and Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, CA 94305.
J Immunol. 2009 Mar 15;182(6):3628-37. doi: 10.4049/jimmunol.0803401.
Humans and chimpanzees have orthologous MHC class I, but few orthologous killer cell Ig-like receptors (KIR). Most divergent are lineage III KIR, which in humans include the inhibitory KIR2DL1 and 2DL2/3 specific for HLA-C. Six lineage III chimpanzee KIR were identified as candidate inhibitory MHC-C receptors and studied using cytolytic assays, to assess the capacity of a defined KIR to function with a defined MHC class I allotype, and direct binding assays with KIR-Fc fusion proteins. Pt-KIR2DL6 and 2DL8 were demonstrated to be inhibitory C1 receptors with a specificity and specificity-determining residue (lysine 44) like KIR2DL3. Analogously, Pt-KIR2DL7 is like KIR2DL1, an inhibitory C2 receptor having methionine 44. Pt-KIR3DL4 and 3DL5 are unusual lineage III KIR with D0 domains, which are also inhibitory C2 receptors with methionine 44. Removal of D0 from KIR3DL, or its addition to KIR2DL, had no effect on KIR function. Pt-KIR2DL9, a fourth inhibitory C2 receptor, has glutamate 44, a previously uncharacterized specificity-determining residue that is absent from human KIR. Reconstruction of the ancestral hominoid KIR sequence shows it encoded lysine 44, indicating that KIR having methionine 44 and glutamate 44 subsequently evolved by independent point substitutions. Thus, MHC-C2-specific KIR have evolved independently on at least two occasions. None of the six chimpanzee KIR studied resembles KIR2DL2, which interacts strongly with C1 and cross-reacts with C2. Whereas human HLA-B allotypes that have functional C1 epitopes are either rare (HLA-B73) or geographically localized (HLA-B46), some 25% of Patr-B allotypes have the C1 epitope and are functional KIR ligands.
人类和黑猩猩拥有直系同源的主要组织相容性复合体I类（MHC class I），但直系同源的杀伤细胞免疫球蛋白样受体（KIR）却很少。差异最大的是III型KIR，在人类中，它包括对HLA - C具有特异性的抑制性KIR2DL1和2DL2/3。已鉴定出6种III型黑猩猩KIR作为候选抑制性MHC - C受体，并通过细胞溶解试验进行研究，以评估特定KIR与特定MHC I类同种异型发挥作用的能力，以及使用KIR - Fc融合蛋白进行直接结合试验。已证明黑猩猩的Pt - KIR2DL6和2DL8是抑制性C1受体，具有与KIR2DL3相似的特异性和特异性决定残基（赖氨酸44）。类似地，Pt - KIR2DL7类似于KIR2DL1，是一种具有甲硫氨酸44的抑制性C2受体。Pt - KIR3DL4和3DL5是具有D0结构域的不同寻常的III型KIR，它们也是具有甲硫氨酸44的抑制性C2受体。从KIR3DL中去除D0，或将其添加到KIR2DL中，对KIR功能没有影响。第四种抑制性C2受体Pt - KIR2DL9具有谷氨酸44，这是人类KIR中不存在的一个先前未表征的特异性决定残基。对原始类人猿KIR序列的重建表明其编码的是赖氨酸44，这表明具有甲硫氨酸44和谷氨酸44的KIR随后通过独立的点突变进化而来。因此，MHC - C2特异性KIR至少在两种情况下独立进化。所研究的6种黑猩猩KIR均与KIR2DL2不同，KIR2DL2与C1强烈相互作用并与C2发生交叉反应。具有功能性C1表位的人类HLA - B同种异型要么罕见（HLA - B73），要么在地理上局限分布（HLA - B46），而约25%的黑猩猩Patr - B同种异型具有C1表位且是功能性KIR配体。
