KIR and HLA in cis and trans cooperatively shape human NK education

顺式和反式的 KIR 和 HLA 合作塑造人类 NK 教育

• 批准号: 9310137
• 负责人: KATHARINE C HSU
• 金额: $ 42.85万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-03 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310137
• 关键词: Acute leukemia; Affinity; Allogenic; Allografting; Binding; Bone Marrow; CD34 gene; Cell Therapy; Cell Transplants; Cell surface; Cells; Chimera organism; Development; Disease; Donor Selection; Education; Energy Transfer; Engraftment; Environment; Evaluation; Exhibits; Exposure to; Failure; Gene Family; Genetic; Goals; HLA Antigens; Hematologic Neoplasms; Hematopoietic; Hematopoietic Stem Cell Transplantation; Histocompatibility Antigens Class I; Human; Immune; Immune system; Immunity; Immunogenetics; Immunology; In Vitro; Inflammatory; Innate Immune System; Interruption; Investigation; Knowledge; Licensing; Ligands; Ligation; Lymphocyte; Mediating; Membrane; Mission; Molecular; Monoclonal Antibodies; Mouse Strains; Mus; Natural Killer Cells; Patients; Play; Population; Proteins; Public Health; RNA Interference; Relapse; Research; Role; Sampling; Shapes; Solid; Stem cells; Study Subject; System; Technology; Testing; Transgenic Mice; Transgenic Organisms; Transplant Recipients; Transplantation; Umbilical Cord Blood; United States National Institutes of Health; Virus; Virus Diseases; cancer cell; cancer therapy; clinically relevant; cytotoxicity; hematopoietic cell transplantation; humanized mouse; in vivo; in vivo Model; killings; leukemia; mouse model; non-Native; novel; receptor; relapse risk; response; therapy design; tumor

PROJECT SUMMARY Natural Killer (NK) cells are highly relevant in the setting of hematopoietic stem cell transplantation (HCT), where their activity can drastically reduce the risk of relapse in leukemia patients. Despite advances in donor selection to minimize transplant complications, leukemia relapse remains one of the most devastating causes of transplant failure. There is a general lack of knowledge of how NK cell populations are educated for effector function, leukemia recognition and clearance. While it is known that interaction between HLA class I molecules and the inhibitory killer Ig-like receptors (KIR) are important for NK education or “licensing” for effector function, the orientation of their interaction, the factors that contribute to the strength of their interaction, and the relative contributions of donor and recipient HLA are not known. A major impediment to fundamental human NK studies has been the lack of in vivo models that faithfully recapitulate NK education. A humanized NOD-RAG2IL2Rγc-/- mouse strain that exhibits HLA-B*27:05 successfully permits engraftment of mature NK cells and development of functional human NK cells from CD34+ stem cells. Preliminary investigations reveal that in vivo environments expressing cognate HLA educate developing and transferred KIR-expressing NK cells and enhance their long-term survival. In parallel, FRET and RNAi technology reveals that cis-interaction between HLA and KIR intrinsic to the cell also facilitates NK education. Evidence that HLA molecules can be transferred onto NK cells from adjacent cells provokes investigation of trogocytosis as a mechanism by which trans HLA may permit education via cis ligation of KIR. Restriction of HLA expression to the hematopoietic or stromal compartments in bone marrow chimeras will help define the relative contributions of donor and recipient HLA to NK licensing and persistence. Receptor- ligand pairs known to bind in trans also interact in cis, and further clarification is required to understand how these interactions influence NK function. Competition between cis-trans binding will test the hypothesis that cis interactions facilitate NK responsiveness by shielding KIR from ligation of trans HLA. NK cells with and without non-native HLA expression will be functionally tested to better understand how trogocytosis contributes to NK education after continuous or interrupted exposure to cognate HLA. Finally, experimental findings from the humanized mouse model and in vitro studies will be verified in a fully human system using NK cells obtained from patients who have received an HLA-mismatched umbilical cord blood transplant. These goals will advance our understanding of fundamental molecular requirements for NK education and acquisition of effector function. A deeper understanding of licensing by HLA provided in cis and trans will inform donor selection in hematopoietic cell transplantation and adoptive NK cell therapies for the treatment of cancer.

项目摘要 天然杀伤（NK）细胞在造血干细胞移植（HCT）的情况下高度相关 他们的活性可以大大减少白血病患者复发的风险。 选择以最大程度地减少移植并发症，白血病复发仍然是最偏差的因果关系之一 透明失败。 功能，白血病识别和清除。 抑制性杀手Ig般的受体（KIR）对于NK教育或“许可”对于效果功能很重要， 它们相互作用的方向，导致相互作用强度的因素以及相对 捐助者和接受者HLA的贡献尚不清楚。 基本人类NK研究的主要阻碍是缺乏体内模型 忠实地向NK教育进行了重组。 成功允许英语NK细胞和功能性人NK细胞的发展 CD34+干细胞。 开发和转移了表达KIR的NK细胞，并在并行中增强了其长期生存 RNAi技术揭示了HLA和KIR固有的CIS相互作用也有助于NK 教育。 将trogocytosis的调查作为一种机制，可以通过trans HLA允许通过KIR的顺式结扎进行教育。 HLA表达对骨髓嵌合体中造血或基质室的限制 将有助于定义捐助者和接受者HLA对NK许可和持久性的相对贡献。 已知在Transo结合的配体对也在顺式中相互作用，需要进一步澄清才能了解如何理解 这些相互作用会影响NK功能。 相互作用可以通过有或不带有trans HLA结扎的KIR来促进NK的疾病。 非本地HLA表达将进行功能测试，以更好地了解Trogotictis如何有助于NK 持续或中断接触同源HLA后的教育。 人性化小鼠模型和体外研究将在完全人类的系统中使用获得的NK细胞进行验证 从接受过HLA不匹配的脐带血移植的患者。 这些目标将提高我们对NK教育基本分子要求的理解 并获得效应函数。 在造血细胞移植和收养NK细胞疗法中为供体选择提供信息 癌症。