A Conserved HIV-1-Derived Peptide Presented by HLA-E Renders Infected T-cells Highly Susceptible to Attack by NKG2A/CD94-Bearing Natural Killer Cells

Major histocompatibility class I (MHC-I)-specific inhibitory receptors on natural killer (NK) cells (iNKRs) tolerize mature NK cell responses toward normal cells. NK cells generate cytolytic responses to virus-infected or malignant target cells with altered or decreased MHC-I surface expression due to the loss of tolerizing ligands. The NKG2A/CD94 iNKR suppresses NK cell responses through recognition of the non-classical MHC-I, HLA-E. We used HIV-infected primary T-cells as targets in an in vitro cytolytic assay with autologous NK cells from healthy donors. In these experiments, primary NKG2A/CD94+ NK cells surprisingly generated the most efficient responses toward HIV-infected T-cells, despite high HLA-E expression on the infected targets. Since certain MHC-I-presented peptides can alter recognition by iNKRs, we hypothesized that HIV-1-derived peptides presented by HLA-E on infected cells may block engagement with NKG2A/CD94, thereby engendering susceptibility to NKG2A/CD94+ NK cells. We demonstrate that HLA-E is capable of presenting a highly conserved peptide from HIV-1 capsid (AISPRTLNA) that is not recognized by NKG2A/CD94. We further confirmed that HLA-C expressed on HIV-infected cells restricts attack by KIR2DL+ CD56dim NK cells, in contrast to the efficient responses by CD56bright NK cells, which express predominantly NKG2A/CD94 and lack KIR2DLs. These findings are important since the use of NK cells was recently proposed to treat latently HIV-1-infected patients in combination with latency reversing agents. Our results provide a mechanistic basis to guide these future clinical studies, suggesting that ex vivo-expanded NKG2A/CD94+ KIR2DL- NK cells may be uniquely beneficial.主要组织相容性复合物I类（MHC-I）特异性抑制性受体（iNKRs）表达于自然杀伤细胞（NK细胞）表面，可使成熟NK细胞对正常细胞产生免疫耐受。NK细胞可对因耐受配体丢失而导致MHC-I表面表达改变或降低的病毒感染细胞或恶性靶细胞产生溶细胞应答。NKG2A/CD94这类iNKR可通过识别非经典MHC-I分子HLA-E来抑制NK细胞应答。本研究以HIV-1感染的原代T细胞为靶标，联合健康供者的自体NK细胞开展体外溶细胞实验。实验结果出乎意料：尽管感染靶细胞表面HLA-E表达水平较高，原代NKG2A/CD94+ NK细胞对HIV-1感染T细胞的溶细胞应答效率却最高。鉴于部分MHC-I呈递的肽段可改变iNKR的识别特性，本研究提出假说：感染细胞表面HLA-E呈递的HIV-1源性肽段，可能会阻断NKG2A/CD94的结合，从而使靶细胞对NKG2A/CD94+ NK细胞产生易感性。本研究证实，HLA-E可呈递一段来自HIV-1衣壳的高度保守肽段（AISPRTLNA），该肽段无法被NKG2A/CD94识别。本研究进一步证实，HIV-1感染细胞表面表达的HLA-C可抑制KIR2DL+ CD56dim NK细胞的杀伤作用；而以高表达NKG2A/CD94且不表达KIR2DLs为特征的CD56bright NK细胞，则可对感染靶细胞产生高效溶细胞应答。鉴于近期有研究提出可联合潜伏期逆转剂，利用NK细胞治疗HIV-1潜伏感染患者，本研究结果具有重要意义。本研究结果为上述未来临床研究提供了机制层面的理论依据，提示体外扩增的NKG2A/CD94+ KIR2DL- NK细胞或可发挥独特的治疗价值。