Sim Malcolm J W, Stowell Janet, Sergeant Ruhena, Altmann Daniel M, Long Eric O, Boyton Rosemary J
Lung Immunology Group, Infectious Diseases and Immunity, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK.
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
Eur J Immunol. 2016 Jan;46(1):185-91. doi: 10.1002/eji.201545757. Epub 2015 Nov 2.
Killer cell immunoglobulin-like receptor/HLA class I (KIR/HLA-I) combinations are associated with disease risk, implicating functional roles for NK cells (NKCs) or KIR(+) T cells. KIR/HLA-I interactions can act through inhibition of NKC activation by target cells and NKC licensing for greater intrinsic responsiveness. We compared licensing conferred by the weaker, HLA-C group 1/KIR2DL3, and the stronger, HLA-C group 2/KIR2DL1, inhibitory combinations. The "rheostat model" predicts weaker licensing by HLA-C1/KIR2DL3 interactions than HLA-C2/KIR2DL1. We analyzed degranulation in NKC subsets expressing single and multiple receptors for HLA-I. NKG2A had the strongest licensing impact, while KIR2DL3, KIR2DL1, and KIR3DL1 were weaker, and not significantly different to each other. Presence of one or two matched HLA-C allotypes did not alter licensing of KIR2DL3(+) and KIR2DL1(+) NKC. Coexpression of activating KIR2DS1 disarmed KIR2DL3(+) and KIR2DL1(+) NKC to a similar extent. KIR3DL1 and NKG2A combined for more enhanced licensing of double-positive NKC than the combination of KIR2DL3 and KIR2DL1. Thus, KIR2DL3 and KIR2DL1 have similar capacity to license NKC, suggesting that inhibitory signal strength and amount of available HLA-C ligands do not correlate with NKC licensing. Altogether, our results show that the basis for disease associations of HLA-C and KIR2DL likely encompasses factors other than licensing.
杀伤细胞免疫球蛋白样受体/HLA I类分子（KIR/HLA-I）组合与疾病风险相关，这暗示了自然杀伤细胞（NKCs）或KIR(+) T细胞的功能作用。KIR/HLA-I相互作用可通过靶细胞对NKC激活的抑制以及NKC的许可作用来发挥功能，从而增强其内在反应性。我们比较了较弱的HLA-C 1组/KIR2DL3和较强的HLA-C 2组/KIR2DL1抑制性组合所赋予的许可作用。“变阻器模型”预测，HLA-C1/KIR2DL3相互作用所赋予的许可作用比HLA-C2/KIR2DL1弱。我们分析了表达单个和多个HLA-I受体的NKC亚群中的脱颗粒情况。NKG2A具有最强的许可作用影响，而KIR2DL3、KIR2DL1和KIR3DL1的作用较弱，且彼此之间无显著差异。存在一种或两种匹配的HLA-C同种异型不会改变KIR2DL3(+)和KIR2DL1(+) NKC的许可作用。激活型KIR2DS1的共表达在相似程度上解除了KIR2DL3(+)和KIR2DL1(+) NKC的武装。与KIR2DL3和KIR2DL1的组合相比，KIR3DL1和NKG2A共同作用可使双阳性NKC的许可作用增强更多。因此，KIR2DL3和KIR2DL1对NKC进行许可的能力相似，这表明抑制信号强度和可用HLA-C配体的数量与NKC许可作用无关。总之，我们的结果表明，HLA-C和KIR2DL与疾病关联的基础可能包含许可作用之外的其他因素。
