Expansion of cytolytic CD8+ natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon γ production
Expansion of cytolytic CD8+ natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon γ production
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DOI：
10.1182/blood.v97.10.2923
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发表时间：
2001-05-15
期刊：
影响因子：
20.3
通讯作者：
Negrin, RS
中科院分区：
文献类型：
--
作者：
Baker, J;Verneris, MR;Negrin, RS
具有自然杀伤细胞表型和功能的T细胞（NKT细胞）已经在人和鼠组织中被描述。在本研究中，通过定时加入干扰素-γ（IFN-γ）、白细胞介素2（IL-2）和抗CD 3单克隆抗体，开发了导致骨髓、胸腺和脾脏中CD 8（+）NKT细胞扩增的培养条件。在培养14至21天后，CD 3（+）、CD 8（+）、α β T细胞受体（+）T细胞的急剧扩增导致约20%至50%的细胞也表达NK标志物NK1.1和DX 5。CD 8（+）NKT细胞对几种肿瘤靶细胞表现出裂解活性，在培养的第14天至第21天裂解率超过90%。通过表达NK 1.1或DX 5的细胞，观察到针对同源和同种异体肿瘤细胞靶的细胞毒性，其中具有最大的裂解活性。扩增的CD 8（+）NKT细胞产生具有高水平IFN-γ和肿瘤坏死因子Oz的T（H）1型细胞因子。CD 8（+）NKT细胞的扩增与CD 1d无关。Ly 49分子仅在少数细胞上表达。单次注射扩增的CD 8（+）NKT细胞能够保护同基因动物免受致命剂量的Bcl 1白血病细胞的伤害。扩增的CD 8（+）NKT细胞产生的移植物抗宿主病（GVHD）远远低于脾细胞跨越主要组织相容性屏障，即使注射的CD 8（+）NKT细胞数量是脾细胞的10倍。GVHD的这种减少与IFN-γ产生有关，因为从IFN-γ敲除动物扩增的细胞引起急性致死性GVHD，而从fas配体、fas、IL-2和穿孔素缺陷的动物扩增的细胞则不引起急性致死性GVHD。这些数据表明，以这种方式扩增的CD 8 + NKT细胞可用于保持移植物抗白血病活性而不引起GVHD。（血。2001;97：2923-2931）（C）2001由美国血液学学会。
T cells with natural killer cell phenotype and function (NKT cells) have been described In both human and murine tissues. In this study, culture conditions were developed that resulted in the expansion of CD8(+) NKT cells from bone marrow, thymus, and spleen by the timed addition of interferon-gamma (IFN-gamma), interleukin 2 (IL-2), and anti-CD3 monoclonal antibody. After 14 to 21 days In culture, dramatic expansion of CD3(+), CD8(+), alpha betaT-cell receptor(+) T cells resulted with approximately 20% to 50% of the cells also expressing the NK markers NK1.1 and DX5. The CD8(+) NKT cells demonstrated lytic activity against several tumor target cells with more than 90% lysis by day 14 to day 21 of culture. Cytotoxicity was observed against both syngeneic and allogeneic tumor cell targets with the greatest lytic activity by the cells expressing either NK1.1 or DX5. The expanded CD8(+) NKT cells produce T(H)1-type cytokines with high levels of IFN-gamma and tumor necrosis factor oz. Expansion of the CD8(+) NKT cells was independent of CD1d. Ly49 molecules were expressed on only a minority of cells. A single injection of expanded CD8(+) NKT cells was capable of protecting syngeneic animals from an otherwise lethal dose of Bcl1 leukemia cells. Expanded CD8(+) NKT cells produced far less graft-versus-host disease (GVHD) than splenocytes across major histocompatibility barriers, even when 10 times the number of CD8(+) NKT cells as compared to splenocytes were injected. This reduction in GVHD was related to IFN-gamma production since cells expanded from IFN-gamma knock-out animals caused acute lethal GVHD, whereas cells expanded from animals defective in fas ligand, fas, IL-2, and perforin did not. These data indicate that CD8+ NKT cells expanded in this fashion could be useful for preserving graft-versus-leukemia activity without causing GVHD. (Blood. 2001;97:2923-2931) (C) 2001 by The American Society of Hematology.