Jackson Elise, Zhang Cindy Xinyu, Kiani Zahra, Lisovsky Irene, Tallon Benjamin, Del Corpo Alexa, Gilbert Louise, Bruneau Julie, Thomas Réjean, Côté Pierre, Trottier Benoit, LeBlanc Roger, Rouleau Danielle, Tremblay Cécile, Tsoukas Christos M, Routy Jean-Pierre, Ni Xiaoyan, Mabanga Tsoarello, Bernard Nicole F
Research Institute of the McGill University Health Center (RI-MUHC), Montreal, Quebec, Canada.
Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
PLoS One. 2017 Sep 22;12(9):e0185160. doi: 10.1371/journal.pone.0185160. eCollection 2017.
Previously, we showed that Killer Immunoglobulin-like Receptor (KIR)3DS1 homozygotes (hmz) are more frequent in HIV exposed seronegative (HESN) than in recently HIV infected (HIV+) individuals. KIR3DS1 encodes an activating Natural Killer (NK) cell receptor (NKR). The link between KIR genotype and HIV outcomes likely arises from the function that NK cells acquire through expression of particular NKRs. An initial screen of 97 HESN and 123 HIV+ subjects for the frequency of KIR region gene carriage observed between-group differences for several telomeric KIR region loci. In a larger set of up to 106 HESN and 439 HIV+ individuals, more HESN than HIV+ subjects were KIR3DS1 homozygotes, lacked a full length KIR2DS4 gene and carried the telomeric group B KIR haplotype motif, TB01. TB01 is characterized by the presence of KIR3DS1, KIR2DL5A, KIR2DS3/5 and KIR2DS1, in linkage disequilibrium with each other. We assessed which of the TB01 encoded KIR gene products contributed to NK cell responsiveness by stimulating NK cells from 8 HIV seronegative KIR3DS1 and TB01 motif homozygotes with 721.221 HLA null cells and evaluating the frequency of KIR3DS1+/-KIR2DL5+/-, KIR3DS1+/-KIR2DS1+/-, KIR3DS1+/-KIR2DS5+/- NK cells secreting IFN-γ and/or expressing CD107a. A higher frequency of NK cells expressing, versus not, KIR3DS1 responded to 721.221 stimulation. KIR2DL5A+, KIR2DS1+ and KIR2DS5+ NK cells did not contribute to 721.221 responses or modulate those by KIR3DS1+ NK cells. Thus, of the TB01 KIR gene products, only KIR3DS1 conferred responsiveness to HLA-null stimulation, demonstrating its ligation can activate ex vivo NK cells.
此前，我们发现，与近期感染HIV（HIV+）的个体相比，暴露于HIV但血清学阴性（HESN）的个体中杀伤细胞免疫球蛋白样受体（KIR）3DS1纯合子（hmz）更为常见。KIR3DS1编码一种活化性自然杀伤（NK）细胞受体（NKR）。KIR基因型与HIV感染结果之间的联系可能源于NK细胞通过特定NKR的表达所获得的功能。对97名HESN个体和123名HIV+个体进行KIR区域基因携带频率的初步筛查，发现几个端粒KIR区域位点存在组间差异。在一组规模更大的多达106名HESN个体和439名HIV+个体中，KIR3DS1纯合子、缺乏全长KIR2DS4基因且携带端粒B组KIR单倍型基序TB01的HESN个体多于HIV+个体。TB01的特征是存在KIR3DS1、KIR2DL5A、KIR2DS3/5和KIR2DS1，它们彼此处于连锁不平衡状态。我们通过用721.221 HLA空白细胞刺激8名HIV血清学阴性KIR3DS1和TB01基序纯合子的NK细胞，并评估分泌IFN-γ和/或表达CD107a的KIR3DS1+/-KIR2DL5+/-、KIR3DS1+/-KIR2DS1+/-、KIR3DS1+/-KIR2DS5+/- NK细胞的频率，来评估TB01编码的哪些KIR基因产物对NK细胞反应性有贡献。与未表达KIR3DS1的NK细胞相比，表达KIR3DS1的NK细胞对721.221刺激的反应频率更高。KIR2DL5A+、KIR2DS1+和KIR2DS5+ NK细胞对721.221刺激无贡献，也不调节KIR3DS1+ NK细胞的反应。因此，在TB01 KIR基因产物中，只有KIR3DS1赋予了对HLA空白刺激的反应性，表明其连接可激活体外NK细胞。
