IL-15及IL-15受体α亚基对肝转移小鼠的治疗作用
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摘要
肝脏是机体的重要器官,承担着多种重要的功能。肝脏的癌变及癌细胞的肝转移,其治疗效果差、死亡率高,已经严重危害人类的健康。肿瘤的免疫治疗已成为肿瘤早期治疗的一个重要的手段,通过激活人体免疫系统来控制肿瘤的生长、消灭癌变细胞、获得抗肿瘤免疫记忆,已成为肿瘤治疗的一个研究热点。其中,白细胞介素15对多种免疫细胞,如记忆T淋巴细胞、自然杀伤细胞、自然杀伤T细胞的发育、分化、激活、增殖等都具有重要的作用,但是,鉴于白细胞介素15在体内半衰期短,以及其特有的通过反式递呈的方式被白细胞介素15受体α亚基递呈给该受体β/γ亚基的特点,在体内使用白细胞介素15进行免疫治疗,虽然取得了一定的成效,但效果并不十分明显。有文献报道,使用制备的白细胞介素15和白细胞介素15受体α亚基复合物进行的免疫治疗,能够使白细胞介素15在体内的活性达到最大值,显著增强了多种淋巴细胞的功能。另外,相对于白细胞介素15的治疗,使用该复合物能够在黑色素瘤的治疗中取得更好的效果,并阐明是增强肿瘤浸润CD8~+ T淋巴细胞的功能来实现抗瘤效应的。
肝脏中富含大量的免疫细胞,因此,肝脏是进行肿瘤免疫治疗的一个极为有利的场所。本研究探讨了白细胞介素15和白细胞介素15受体α亚基复合物在肝转移小鼠中的治疗效果,通过分子生物学的方法成功构建了含有白细胞介素15和白细胞介素15受体α亚基复合物基因的质粒并检测所构建的质粒在体内对CD8~+ T细胞和NK细胞的作用,利用CT26小鼠结直肠癌细胞系肝门静脉注射成功建立肝转移小鼠模型并通过尾静脉高压注射质粒来进行免疫治疗,寻找到该肿瘤模型最佳的肿瘤生长剂量,分析了该模型中淋巴细胞表面程序性死亡因子1的表达、调节性T细胞的数量,并分析了利用该复合物在肿瘤预防、治疗中的效果,最后通过特异淋巴细胞删除实验来寻找白细胞介素15所介导的免疫杀伤的机制,这些研究为白细胞介素15和白细胞介素15受体α亚基复合物在肝癌临床上的治疗以及后续的免疫联合治疗研究提供了重要的理论依据。主要结果和结论如下:
⑴成功构建白细胞介素15和白细胞介素15受体α亚基复合物质粒,该构建的质粒具有白细胞介素15的功能,能促进体内CD8~+T细胞和NK细胞的增殖。
⑵CT26小鼠结直肠癌细胞系通过肝门静脉注射所构建的Balb/c肝转移小鼠中,用于随后免疫治疗的癌细胞系的最佳剂量为1×10~5。在该肿瘤模型中,CD8~+、CD4~+T淋巴细胞和NK细胞的数量随着肿瘤的进展而增加;同时,CD8~+和CD4~+T淋巴细胞膜表面的程序性死亡因子1的表达水平上调,调节性T细胞的数量也会增多。
⑶通过尾静脉给Balb/c小鼠注射白细胞介素15及白细胞介素15受体α亚基复合物质粒后,再通过肝门静脉注射肿瘤细胞,该小鼠肝脏没有肿瘤发生,与对照组(注射无白细胞介素15及白细胞介素15受体α亚基复合物质粒,注射肿瘤细胞)的肝脏成显著差异(有肿瘤发生);同时,该组的CD8~+与CD4~+ T淋巴细胞的比例显著提高。因此,白细胞介素15及白细胞介素15受体α亚基复合物能有效的预防肿瘤的发生。
⑷通过注射白细胞介素15及白细胞介素15受体α亚基复合物质粒对肝转移小鼠治疗后,肝脏的观测以及肝重的统计学分析表明,治疗组的肝脏仅有少量的肿瘤,与对照组有显著差异。因此,白细胞介素15及白细胞介素15受体α亚基复合物在肝转移小鼠中的治疗效果很好。
⑸分别特异性删除CD8~+T淋巴细胞和NK细胞,删除CD8~+T细胞后肿瘤不能消除,而删除NK细胞后肿瘤可被消除,从而证实介导抗肝脏肿瘤效应的机制主要是通过CD8~+T淋巴细胞介导的,而不是NK细胞介导的。
The liver is a vital organ of the body, and responsible for many important functions. The treatment effect on liver cancer and metastasis of liver cancer cells is poor with a high mortality rate, which has serious harm human health. Tumor immune therapy has become one of the important tumor early treatment means, through activating the body's immune system to control the growth of tumors, destroy cancerous cells, obtain anti-tumor immune memory, has become a cancer treatment research hotspot. Among them, interleukin 15 to a variety of interleukin immune cells, such as memory T lymphocytes, natural killer cells, natural killer T cell development, differentiation, activation, proliferation has important effect, however, between interleukin 15 in the body and the short half-life endemic in by way of trans deferred by interleukin 15 receptor alpha subunit, assume this receptor deferred the beta/gamma subunit characteristics and the body use interleukin 15 immune therapy, although which have made some achievements, the effect is not very obvious. Have reports in the literature, use of the preparation of interleukin 15 and interleukin 15 receptor alpha subunit, immune therapy, the compound could make interleukin 15 in the body, maximum significantly enhance activity of a variety of lymphocyte function. In addition, relative to the treatment of interleukin 15, use the complexes in melanoma can the treatment of better results, and expound is enhancing tumor infiltration CD8~+ T lymphocyte function to realize an anti-tumor effect.
Liver rich in a lot of immune cells, therefore, liver cancer immunotherapy is an extremely advantageous place. This study explores the interleukin 15 and interleukin 15 receptor alpha subunit, complex in the treatment of liver metastasis model, through the effect of molecular biology method successfully constructed contains interleukin 15 and interleukin 15 receptor alpha subunit, complex genetic plasmid and testing the plasmid constructed in the body to CD8~+T cells and the role of NK cells in mice, using CT26 colorectal cancer cell lines hepatoportal injection successfully established a liver metastases model and through the tail vein high-pressure injection plasmid for immune therapy, and seeks to this model optimal tumor growth doses and analysis of the tumor model lymphocytes apoptosis factor 1 on the expression, the number of regulatory T cells, and the analysis using the complex in cancer prevention and treatment of effect, finally through specific lymphocytes delete experiment to find interleukin 15 mediated the mechanism of immune killer, these studies for interleukin 15 and interleukin 15 receptor alpha subunit, complex clinical treatment in liver cancer and subsequent immune combination therapy research offers important theory basis. Main results are as follows:
⑴Success constructing interleukin 15 and interleukin 15 receptor alpha and matrix composite material grain, this building with the plasmid interleukin 15 function, can promote body CD8~+ T cells and NK cell proliferation;
⑵CT26 colorectal cancer cells in mice by hepatoportal injection established Balb/c liver metastasis immune therapy mouse models of the best dose for 1×10~5, in the tumor model, CD8, CD4 T lymphocytes, and the number of NK cells with cancer development, meanwhile, CD8 increases CD4 T lymphocyte membrane surface and apoptosis factor1 expression level rise, the number of regulatory T cells will increase;
⑶After inject the plasmid of interleukin 15 and interleukin 15 receptorαchain, construct the model of hepatic metastases, this group have no tumor occoured. At the same time, the ratio of CD8/CD4 of this group is obviously improving. So interleukin 15 can effective control the scale of the occurrence of cancer prevention;
⑷Through the treatment of liver after the macroscopic observation and weight of statistical analysis, the group of super IL-15 have little tumor while the control group have more. So liver interleukin 15 and interleukin 15 receptor alpha subunit, complex in the treatment of liver metastasis model effect is very good;
⑸Specificity delete CD8~+T cells and NK cells, the group of delete CD8~+T cells not prevent tumor while the group of delete NK cells have still little tumor, confirmed mediating NK cells and resistance to liver tumor effect mainly by CD8~+T lymphocytes instead of NK cells.
肝脏中富含大量的免疫细胞,因此,肝脏是进行肿瘤免疫治疗的一个极为有利的场所。本研究探讨了白细胞介素15和白细胞介素15受体α亚基复合物在肝转移小鼠中的治疗效果,通过分子生物学的方法成功构建了含有白细胞介素15和白细胞介素15受体α亚基复合物基因的质粒并检测所构建的质粒在体内对CD8~+ T细胞和NK细胞的作用,利用CT26小鼠结直肠癌细胞系肝门静脉注射成功建立肝转移小鼠模型并通过尾静脉高压注射质粒来进行免疫治疗,寻找到该肿瘤模型最佳的肿瘤生长剂量,分析了该模型中淋巴细胞表面程序性死亡因子1的表达、调节性T细胞的数量,并分析了利用该复合物在肿瘤预防、治疗中的效果,最后通过特异淋巴细胞删除实验来寻找白细胞介素15所介导的免疫杀伤的机制,这些研究为白细胞介素15和白细胞介素15受体α亚基复合物在肝癌临床上的治疗以及后续的免疫联合治疗研究提供了重要的理论依据。主要结果和结论如下:
⑴成功构建白细胞介素15和白细胞介素15受体α亚基复合物质粒,该构建的质粒具有白细胞介素15的功能,能促进体内CD8~+T细胞和NK细胞的增殖。
⑵CT26小鼠结直肠癌细胞系通过肝门静脉注射所构建的Balb/c肝转移小鼠中,用于随后免疫治疗的癌细胞系的最佳剂量为1×10~5。在该肿瘤模型中,CD8~+、CD4~+T淋巴细胞和NK细胞的数量随着肿瘤的进展而增加;同时,CD8~+和CD4~+T淋巴细胞膜表面的程序性死亡因子1的表达水平上调,调节性T细胞的数量也会增多。
⑶通过尾静脉给Balb/c小鼠注射白细胞介素15及白细胞介素15受体α亚基复合物质粒后,再通过肝门静脉注射肿瘤细胞,该小鼠肝脏没有肿瘤发生,与对照组(注射无白细胞介素15及白细胞介素15受体α亚基复合物质粒,注射肿瘤细胞)的肝脏成显著差异(有肿瘤发生);同时,该组的CD8~+与CD4~+ T淋巴细胞的比例显著提高。因此,白细胞介素15及白细胞介素15受体α亚基复合物能有效的预防肿瘤的发生。
⑷通过注射白细胞介素15及白细胞介素15受体α亚基复合物质粒对肝转移小鼠治疗后,肝脏的观测以及肝重的统计学分析表明,治疗组的肝脏仅有少量的肿瘤,与对照组有显著差异。因此,白细胞介素15及白细胞介素15受体α亚基复合物在肝转移小鼠中的治疗效果很好。
⑸分别特异性删除CD8~+T淋巴细胞和NK细胞,删除CD8~+T细胞后肿瘤不能消除,而删除NK细胞后肿瘤可被消除,从而证实介导抗肝脏肿瘤效应的机制主要是通过CD8~+T淋巴细胞介导的,而不是NK细胞介导的。
The liver is a vital organ of the body, and responsible for many important functions. The treatment effect on liver cancer and metastasis of liver cancer cells is poor with a high mortality rate, which has serious harm human health. Tumor immune therapy has become one of the important tumor early treatment means, through activating the body's immune system to control the growth of tumors, destroy cancerous cells, obtain anti-tumor immune memory, has become a cancer treatment research hotspot. Among them, interleukin 15 to a variety of interleukin immune cells, such as memory T lymphocytes, natural killer cells, natural killer T cell development, differentiation, activation, proliferation has important effect, however, between interleukin 15 in the body and the short half-life endemic in by way of trans deferred by interleukin 15 receptor alpha subunit, assume this receptor deferred the beta/gamma subunit characteristics and the body use interleukin 15 immune therapy, although which have made some achievements, the effect is not very obvious. Have reports in the literature, use of the preparation of interleukin 15 and interleukin 15 receptor alpha subunit, immune therapy, the compound could make interleukin 15 in the body, maximum significantly enhance activity of a variety of lymphocyte function. In addition, relative to the treatment of interleukin 15, use the complexes in melanoma can the treatment of better results, and expound is enhancing tumor infiltration CD8~+ T lymphocyte function to realize an anti-tumor effect.
Liver rich in a lot of immune cells, therefore, liver cancer immunotherapy is an extremely advantageous place. This study explores the interleukin 15 and interleukin 15 receptor alpha subunit, complex in the treatment of liver metastasis model, through the effect of molecular biology method successfully constructed contains interleukin 15 and interleukin 15 receptor alpha subunit, complex genetic plasmid and testing the plasmid constructed in the body to CD8~+T cells and the role of NK cells in mice, using CT26 colorectal cancer cell lines hepatoportal injection successfully established a liver metastases model and through the tail vein high-pressure injection plasmid for immune therapy, and seeks to this model optimal tumor growth doses and analysis of the tumor model lymphocytes apoptosis factor 1 on the expression, the number of regulatory T cells, and the analysis using the complex in cancer prevention and treatment of effect, finally through specific lymphocytes delete experiment to find interleukin 15 mediated the mechanism of immune killer, these studies for interleukin 15 and interleukin 15 receptor alpha subunit, complex clinical treatment in liver cancer and subsequent immune combination therapy research offers important theory basis. Main results are as follows:
⑴Success constructing interleukin 15 and interleukin 15 receptor alpha and matrix composite material grain, this building with the plasmid interleukin 15 function, can promote body CD8~+ T cells and NK cell proliferation;
⑵CT26 colorectal cancer cells in mice by hepatoportal injection established Balb/c liver metastasis immune therapy mouse models of the best dose for 1×10~5, in the tumor model, CD8, CD4 T lymphocytes, and the number of NK cells with cancer development, meanwhile, CD8 increases CD4 T lymphocyte membrane surface and apoptosis factor1 expression level rise, the number of regulatory T cells will increase;
⑶After inject the plasmid of interleukin 15 and interleukin 15 receptorαchain, construct the model of hepatic metastases, this group have no tumor occoured. At the same time, the ratio of CD8/CD4 of this group is obviously improving. So interleukin 15 can effective control the scale of the occurrence of cancer prevention;
⑷Through the treatment of liver after the macroscopic observation and weight of statistical analysis, the group of super IL-15 have little tumor while the control group have more. So liver interleukin 15 and interleukin 15 receptor alpha subunit, complex in the treatment of liver metastasis model effect is very good;
⑸Specificity delete CD8~+T cells and NK cells, the group of delete CD8~+T cells not prevent tumor while the group of delete NK cells have still little tumor, confirmed mediating NK cells and resistance to liver tumor effect mainly by CD8~+T lymphocytes instead of NK cells.
引文
[1] Mowat AM. Anatomical basis of tolerance and immunity to intestinal antigens[J]. Nat Rev Immunol, 2003,3(4):331-341.
[2] Norris S, Collins C, Doherty DG, et al. Resident human hepatitis lymphocytes are phenotypically different from circulating lymphocytes[J]. J Hepatol, 1998,28(1):84-96
[3]田志刚.肝脏NK/NKT细胞及其生物学意义.第二军医大学学报[J],2002,23(10):10~57-1060
[4] Doherty DG, O'Farrelly C. Innate and adaptive lymphoid cells In the human liver[J]. Immunol Rev, 2000,174:5-20.
[5] Wiltrout RH. Regulation and antimetastatic functions of liver associated natural killer cells[J]. Immunol Rev, 2000,174:63-76.
[6] Seki S, Habu Y, Kawamura T, et al. The liver as a crucial organ in the first line of host defense:the roles of Kupffer cells,natural killer(NK)cells and NK1.1Ag~+T cells in T helper 1 immune responses[J]. Immunol Rev, 2000,174:35-46
[7] Golden-Mason L, O'Farrelly C. Having it all Stem cells,haematops is and lymphopoiesis in adult human liver[J]. Immunol Cell Biol, 2002,80(1):45-51.
[8] Befeler A S, Di Bisceglie A M. Hepatocellular carcinoma:diagnosis and treatment[J]. Gastroenterology, 2002,122(6):1609-1619.
[9] Verslype C, Van Cutsem E, Dicato M,et a1.The man agement of hepatocellular carcinoma.Current expert opinion and recommendations derived from the 10th World Congress on Gastrointestinal Cancer,Barcelona, 2008. Annals of Oncology, 2009,20(Supplement 7).
[10] Blugartl H, Fong Y. Surgical options in treatment of hepatic metastasis from colorectal cancer[J]. Curt Probl Surg, 1995,32(5): 27
[11] Grabstein KH, Eisenman J, Shanebeck K, et a1. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin 2 receptor[J]. Science, 1994,264(5161): 965-968.
[12] Meazza R, Verdiani S, Biassoni R, et al. Identification of a novel interleukin-15 (IL-15) transcript isoform generated by alternative splicing in human small cell lung cancer cell lines[J]. Oncogene, 1996,12(10): 2187-2192.
[13] Anderson DM, Johnson L, Glaccum MB, et al. Chromosomal assignment and genomic structure of IL-15[J]. Genomics, 1995,25(3): 701-706.
[14] Krause H, Krause H, Jandrig B, et al. Genomic structure and chromosomal localization of the human interleukin 15 gene IL-15[J]. Cytokine, 1996,8(9): 667-674.
[15] Lee YB, Satoh J, Walker DG, et al. Interleukin 15 gene expression in human astrocytes and microglia in culture[J]. Neuroreport, 1996,7(5): 1062-1066.
[16] Giri JG, Anderson DM, Kumaki S, et al. IL-15, a novel T cell growth factor that shares activities andreceptor components with IL-2[J]. J Leukoc Biol, 1995,57(5): 763–766.
[17] Bamford R. N., A. P. Battiata, J. D. Burton, et al. Interleukin (IL) 15/IL-T production by the adult T-cell leukemia cell line HuT-102 is associated with a human T-cell lymphotrophic virus type I region/IL-15 fusion message that lacks many upstream AUGs that normally attenuates IL-15 mRNA translation[J]. Proc. Natl. Acad. Sci. USA 1996,93(7): 2897–2902.
[18] Nishimura H., A. Fujimoto, N. Tamura, et al. A novel autoregulatory mechanism for transcriptional activation of the IL-15 gene by a nonsecretable isoform of IL-15 generated by alternative splicing[J]. FASEB J 2005,19(1): 19–28.
[19] Villinger F., R. Miller, K. Mori, et al. IL-15 is superior to IL-2 in the generation of long-lived antigen specific memory CD4 and CD8 T cells in rhesus macaques[J].Vaccine 2004,22(25-26): 3510–3521.
[20] Cosman D, Kumaki S, Ahdieh M, et al. Interleukin 15 and its receptor[J]. Ciba Found Symp 1995,195:221-229
[21] J.G. Giri, S. Kumaki, M. Ahdieh, et al. Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor[J]. EMBO J 1995,14(15):3654–3663.
[22] D.M. Anderson, S. Kumaki, M. Ahdieh, et al. Tometsko and A. Loomis et al., Functional characterization of the human interleukin-15 receptor alpha chain and close linkage of IL-15RA and IL2RA genes[J]. J Biol Chem 1995,270(50):29862–29869.
[23] T.A. Waldmann. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design[J]. Nat Rev Immunol 2006,6(8):595–601.
[24] S. Bulfone-Paus, E. Bulanova, T. Pohl, et al. Death deflected: IL-15 inhibits TNF-alpha-mediated apoptosis in fibroblasts by TRAF2 recruitment to the IL-15Ralpha chain[J]. FASEB J 1999,13(12):1575–1585.
[25] V. Budagian, E. Bulanova, Z. Orinska, et al. A promiscuous liaison between IL-15 receptor and Axl receptor tyrosine kinase in cell death control[J]. EMBO J 2005,24(24):4260–4270.
[26] E. Bulanova, V. Budagian, T. Pohl, et al. The IL-15R alpha chain signals through association with Syk in human B cells[J]. J Immunol 2001,167(11):6292–6302.
[27] R. Pereno, A. Gaggero, M. Scudeletti, et al. IL-15/IL-15R alpha intracellular trafficking in human cells and protection from apoptosis[J]. Ann N Y Acad Sci 1999,876:236–245.
[28] Lodolce JP, Burkett PR, Boone DL, et al. 2001. T cell-independent interleukin 15Rαsignals are required for bystander proliferation[J]. J. Exp. Med 2001,194(8):1187–1194
[29] Burkett PR, Koka R, Chien M, et al. IL-15Rαexpression on CD8~+ T cells is dispensable for T cell memory[J]. Proc. Natl. Acad. Sci. 2003,100(8):4724–4729
[30] Schluns KS, Klonowski KD, Lefrancois L. Transregulation of memory CD8 T-cell proliferation by IL-15Rαbone marrow-derived cells[J]. Blood 2004,103(3):988–994
[31] Giri JG, Ahdieh M, Eisenman J, et al. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15[J]. EMBO J 1994,13(12):2822–2830.
[32] Dubois S, Mariner J, Waldmann TA, et al. IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells[J]. Immunity 2002,17(5):537–547.
[33] Burkett PR, Koka R, Chien M, et al. Coordinate expression and trans presentation of interleukin (IL)-15Rαand IL-15 supports natural killer cell and memory CD8~+ T cell homeostasis[J]. J. Exp. Med 2004,200(7):825–834
[34] Musso T, Calosso L, Zucca M, et al. Human monocytes constitutively express membrane-bound, biologically active,and interferon-gamma-upregulated interleukin-15[J]. Blood,1999,93 :3531–3539.
[35] Neely GG, Robbins SM, Amankwah EK, et al. Lipopolysaccharide-stimulated or granulocyte-macrophage colonystimulating factor-stimulated monocytes rapidly express biologically active IL-15 on their cell surface independent of new protein synthesis[J]. J Immunol 2001,167(9):5011–5017.
[36] Sandau MM, Schluns KS, Lefrancois L, et al. Cutting edge: transpresentation of IL-15 by bone marrow-derived cells necessitates expression of IL-15 and IL-15Rαby the same cells[J]. J. Immunol 2004,173(11):6537–6541
[37] Koka R, Burkett P, Chien M, et al. Cutting edge: murine dendritic cells require IL-15Rαto prime NK cells[J]. J. Immunol 2004,173(6):3594–3598
[38] Dubois SP, Waldmann TA, Muller JR. Survival adjustment of mature dendritic cells by IL-15[J]. Proc. Natl. Acad. Sci 2005,102(24):8662–8667
[39] Spencer W. Stonier, Kimberly S. Schluns. Trans-presentation: A novel mechanism regulating IL-15 delivery and responses[J]. Immunology Letters 2010,127(2):85–92
[40] Ilangumaran S, Ramanathan S, Ning T, et al. Suppressor of cytokine signaling 1 attenuates IL-15 receptor signaling in CD8~+ thymocytes[J]. Blood 2003,102(12):4115–4122
[41] Kennedy MK, Glaccum M, Brown SN, et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice[J]. J. Exp.Med. 2000,191(5):771–780
[42] Averil Ma, Rima Koka, Patrick Burkett, et al.. Diverse Functions of IL-2, IL-15, and IL-7 in Lymphoid Homeostasis[J]. Annu. Rev. Immunol 2006,24:657–679
[43] Marrack P, Kappler J. Control of T cell viability[J]. Annu. Rev. Immunol 2004,22:765–787
[44] Lodolce JP, Boone DL, Chai S, et al. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation[J]. Immunity 1998,9(5):669–676
[45] Vella AT, Dow S, Potter TA, et al. Cytokine-induced survival of activated T cells in vitro and in vivo[J]. Proc. Natl. Acad. Sci. 1998,95(7):3810–3815
[46] Zhang X, Sun S, Hwang I, et al. Potent and selective stimulation of memory-phenotype CD8~+ T cells in vivo by IL-15[J]. Immunity 1998, 8(5):591–599
[47] Schluns KS, Williams K, Ma A, et al. Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells[J]. J. Immunol 2002,168(10):4827–4831
[48] Becker TC, Wherry EJ, Boone D, et al. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells[J]. J. Exp. Med 2002,195(12):1541–1548
[49] Tagaya Y, Burton JD, Miyamoto Y, et al. Identification of a novel receptor/ signal transduction pathway for IL-15/T in mast cells[J]. EMBO J 1996,15(18):4928–4939
[50] Ku CC, Murakami M, Sakamoto A, et al. Control of homeostasis of CD8~+ memory T cells byopposing cytokines[J]. Science 2000,288(5466):675–678
[51] Goldrath AW, Sivakumar PV, Glaccum M, et al. Cytokine requirements for acute and basal homeostatic proliferation of naive and memory CD8~+ T cells[J]. J. Exp. Med 2002,195(12):1515–1522
[52] Weninger W, Crowley MA, Manjunath N, et al. Migratory properties of naive, effector, and memory CD8~+ T cells[J]. J. Exp. Med 2001,194(7):953–966
[53] Loza MJ, Peters SP, Zangrilli JG, et al. Distinction between IL-13~+ and IFN-γ~+ natural killer cells and regulation of their pool size by IL-4[J]. Eur. J. Immunol 2002, 32(2):413–23
[54] Miller JS, Alley KA, McGlave P. Differentiation of natural killer (NK) cells from human primitive marrow progenitors in a stroma-based long-term culture system: identification of a CD34~+7~+ NK progenitor[J]. Blood 1994,83(9):2594–2601
[55] Mrozek E, Anderson P, Caligiuri MA. Role of interleukin-15 in the development of human CD56~+ natural killer cells from CD34~+ hematopoietic progenitor cells[J]. Blood 1996,87(7):2632–2640
[56] Williams NS, MooreTA, Schatzle JD, et al. Generation of lytic natural killer 1.1, Ly-49? cells from multipotential murine bone marrow progenitors in a stroma-free culture: definition of cytokine requirements and developmental intermediates[J]. J. Exp. Med. 1997,186(9):1609–1614
[57] Maki K, Sunaga S, Komagata Y, et al. Interleukin 7 receptor deficient mice lackγδT cells[J]. Proc. Natl. Acad. Sci. 1996, 93(14):7172–7177
[58] Kundig TM, Schorle H, Bachmann MF, et al. Immune responses in interleukin-2-deficient mice[J]. Science 1993,262(5136):1059–1061
[59] Vosshenrich CA, Ranson T, Samson SI, et al. Roles for common cytokine receptorγ-chain-dependent cytokines in the generation, differentiation, and maturation of NK cell precursors and peripheral NK cells in vivo[J]. J. Immunol. 2005,174(3):1213–1221
[60] Kawamura T, Koka R, Ma A, et al. Differential roles for IL-15Rα-chain in NK cell development and Ly-49 induction[J]. J. Immunol. 2003,171(10):5085–5090
[61] Saleh A, Davies GE, Pascal V, et al. Identification of probabilistic transcriptional switches in the Ly49 gene cluster: a eukaryotic mechanism for selective gene activation[J]. Immunity 2004,21(1):55–66
[62] Arase H, Mocarski ES, Campbell AE, et al. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors[J]. Science 2002,296(5571):1323–1326
[63] Cooper MA,Bush JE, Fehniger TA, et al. In vivo evidence for a dependence on interleukin 15 for survival of natural killer cells[J]. Blood 2002,100(10):3633–3638
[64] Koka R, Burkett PR, Chien M, et al. Interleukin (IL)-15Rα- deficient natural killer cells survive in normal but not IL-15Rα-deficient mice[J]. J. Exp.Med. 2003,197(8):977–984
[65] Minagawa M, Watanabe H, Miyaji C, et al. Enforced expression of Bcl-2 restores the number of NK cells, but does not rescue the impaired development of NKT cells or intraepithelial lymphocytes, in IL-2/IL-15 receptorβ-chain-deficient mice[J]. J. Immunol. 2002,169(8):4153–4160
[66] Nguyen KB, Salazar-Mather TP, Dalod MY, et al. Coordinated and distinct roles for IFN-αβ, IL-12, and IL-15 regulation of NK cell responses to viral infection[J]. J. Immunol. 2002,169(8):4279–4287
[67] Fawaz LM, Sharif-Askari E, Menezes J. Up-regulation of NK cytotoxic activity via IL-15 induction bydifferent viruses: a comparative study[J]. J. Immunol. 1999,163(8):4473–80
[68] Gri G, Chiodoni C, Gallo E, et al. Antitumor effect of interleukin (IL)-12 in the absence of endogenous IFN-γ: a role for intrinsic tumor immunogenicity and IL-15[J]. Cancer Res. 2002,62(15):4390–4397
[69] Comes A, Di Carlo E, Musiani P, et al. IFN-γ-independent synergistic effects of IL-12 and IL-15 induce anti-tumor immune responses in syngeneic mice[J]. Eur. J. Immunol. 2002,32(7):1914–1923
[70] Biber JL, Jabbour S, Parihar R, et al. Administration of two macrophage-derived interferon-γ-inducing factors (IL-12 and IL-15) induces a lethal systemic inflammatory response in mice that is dependent on natural killer cells but does not require interferon-γ[J]. Cell. Immunol. 2002,216(1-2):31–42
[71] Gerosa F, Baldani-Guerra B, Nisii C, et al. Reciprocal activating interaction between natural killer cells and dendritic cells[J]. J. Exp. Med. 2002,195(3):327–333
[72] Fernandez NC, Lozier A, Flament C, et al. Dendritic cells directly triggerNKcell functions: cross-talk relevant in innate anti-tumor immune responses in vivo[J]. Nat. Med. 1999,5(4):405–411
[73] Ferlazzo G, Tsang ML, Moretta L, et al. Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells[J]. J. Exp. Med. 2002,195(3):343–351
[74] Piccioli D, Sbrana S, Melandri E, et al. Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells[J]. J. Exp. Med. 2002,195(3):335–341
[75] Andrews DM, Scalzo AA, Yokoyama WM, et al. Functional interactions between dendritic cells and NK cells during viral infection[J]. Nat. Immunol. 2003,4(2):175–181
[76] Ferrari-Lacraz S.E. Zanelli, M. Neuberg, et al. Targeting IL-15 receptor-bearing cells with an antagonist mutant IL-15/Fc protein prevents disease development and progression in murine collagen-induced arthritis[J]. J. Immunol. 2004,173(9): 5818–5826.
[77] Ruchatz H., B. P. Leung, X. Q. Wei, et al. Soluble IL-15 receptorα-chain administration prevents murine collagen-induced arthritis: a role for IL-15 in development of antigen-induced immunopathology[J]. J. Immunol. 1998,160(11): 5654–5660.
[78] Smith X. G., E. M. Bolton, H. Ruchatz, et al. Selective blockade of IL-15 by soluble IL-15 receptorα-chain enhances cardiac allograft survival[J]. J. Immunol. 2000,165(6): 3444–3450.
[79] Khan I. A., L. H. Kasper. IL-15 augments CD8 T cell-mediatedimmunity against Toxoplasma gondii infection in mice[J]. J. Immunol. 1996,157(5):2103–2108.
[80] Tsunobuchi H., H. Nishimura, F. Goshima, et al. A protective role of interleukin-15 in a mouse model for systemic infection with herpes simplex virus[J].Virology 2000,275(1): 57–66.
[81] Maeurer M. J., P. Trinder, G. Hommel, et al. Interleukin-7 or interleukin-15 enhances survival of Mycobacterium tuberculosis-infected mice[J]. Infect. Immun. 2000,68(5): 2962–2970.
[82] Umemura M., H. Nishimura, K. Hirose, et al. Overexpression of IL-15 in vivo enhances protection against Mycobacterium bovis bacillus Calmette-Guerin infection via augmentation of NK and T cytotoxic 1 responses[J]. J. Immunol. 2000,167(2): 946–956.
[83] Rubinstein M. P., A. N. Kadima, M. L. Salem, et al. Systemic administration of IL-15 augments theantigenspecific primary CD8 T cell response following vaccination with peptide-pulsed dendritic cells[J]. J. Immunol. 2002,169(9): 4928–4935.
[84] Oh S., J. A. Berzofsky, D. S. Burke, et al. Coadministration of HIV vaccine vectors with vaccinia viruses expressing IL-15 but not IL-2 induces long-lasting cellular immunity[J]. Proc. Natl. Acad. Sci. 2003,100(6): 3392–3397.
[85] Hiromatsu T., T. Yajima, T. Matsuguchi, et al. Overexpression of interleukin-15 protects against Escherichia coli-induced shock accompanied by inhibition of tumor necrosis factor-α-induced apoptosis[J]. J. Infect. Dis. 2003,187(9): 1442–1451.
[86] Toka F. N., B. T. Rouse. Mucosal application of plasmid-encoded IL-15 sustains a highly protective anti-Herpes simplex virus immunity[J]. J. Leukocyte Biol. 2005,78(1): 178–186.
[87] Melchionda F., T. J. Fry, M. J. Milliron, et al. Adjuvant IL-7 or IL-15 overcomes immunodominance and improves survival of the CD8 memory cell pool[J]. J. Clin. Invest. 2005,115(5): 1177–1187.
[88]Bamford R. N., A. P. DeFilippis, N. Azimi, et al. The 5 untranslated region, signal peptide, and the coding sequence of the carboxyl terminus of IL-15 participate in its multifaceted translational control[J]. J. Immunol. 1998,160(9): 4418–4426.
[89] Mastroianni C. M., G. d’Ettorre, G. Forcina, et al. Interleukin-15 enhances neutrophil functional activity in patients with human immunodeficiency virus infection[J]. Blood 2000,96(5): 1979–1984.
[90] Chitnis V., R. Pahwa, S. Pahwa . Determinants of HIV-specific CD8 T-cell responses in HIV-infected pediatric patients and enhancement of HIVgag-specific responses with exogenous IL-15[J]. Clin. Immunol. 2003,107(1): 36–45.
[91] Mueller Y. M., P. M. Bojczuk, E. S. Halstead, et al. IL-15 enhances survival and function of HIV-specific CD8 T cells[J]. Blood 2003,101(3): 1024–1029.
[92] Castelli J., E. K. Thomas, M. Gilliet, et al. Mature dendritic cells can enhance CD8 cell noncytotoxic anti-HIV responses: the role of IL-15[J]. Blood 2004,103(7): 2699–2704.
[93] Lum J. J., D. J. Schnepple, Z. Nie, et al. Differential effects of interleukin-7 and interleukin-15 on NK cell anti-human immunodeficiency virus activity[J]. J. Virol. 2004,78(11): 6033–6042.
[94] Forcina G., G. d’Ettorre, C. M. Mastroianni, et al. Interleukin-15 modulates interferon-γandβ-chemokine production in patients with HIV infection: implications for immune-based therapy[J]. Cytokine 2004,25(6): 283–290.
[95] Alpdogan O., J. M. Eng, S. J. Muriglan, et al. Interleukin-15 enhances immune reconstitution after allogenic bone marrow transplantation[J]. Blood 2005,105(2): 865–873.
[96] Chapoval A. I., J. A. Fuller, S. G. Kremlev, et al. Combination chemotherapy and IL-15 administration induce permanent tumor regression in a mouse lung tumor model: NK and T cell-mediated effects antagonized by B cells[J]. J. Immunol. 1998,161(12): 6977–6984.
[97] Wysocka M., B. M. Benoit, S. Newton, et al. Enhancement of the host immune responses in cutaneous T-cell lymphoma by CpG oligodeoxynucleotides and IL-15[J]. Blood 2004,104(13):4142–4149.
[98] Klebanoff C. A., S. E. Finkelstein, D. R. Surman, et al. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8 T cells[J].Proc. Natl. Acad. Sci. 2004, 101(7): 1969–1974.
[99] Teague RM, Sather BD, Sacks JA, et al. Interleukin-15 rescues tolerant CD8~+ T cells for use in adoptive immunotherapy of established tumors[J]. Nat Med 2006,12(3):335–41.
[100] Evans R, Fuller JA, Christianson G, et al. IL-15 mediates anti-tumor effects after cyclophosphamide injection of tumor-bearing mice and enhances adoptive immunotherapy: the potential role of NK cell subpopulations[J]. Cell Immunol 1997,179(1):66–73.
[101] Stoklasek TA, Schluns KS, Lefrancois L. Combined IL-15/IL-15Ra immunotherapy maximizes IL-15 activity in vivo[J]. J Immunol 2006,177(9):6072–6080.
[102] Shannon J. Turley. Interleukin-15/Interleukin-15RA Complexes Promote Destruction of Established Tumors by Reviving Tumor-Resident CD8 T Cells[J]. Cancer Res 2008,68(8): 2972-2983
[103] Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection and immunosubversion[J]. Nat Rev Immunol 2006,6(10):715–727.
[104] Pardoll D. Does the immune system see tumors as foreign or self[J]? Annu Rev Immunol 2003,21:807–839.
[105] Street SE, Hayakawa Y, Zhan Y, et al. Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and gy T cells[J]. J Exp Med 2004,199(6):879–884.
[106] Diefenbach A, Jensen ER, Jamieson AM, et al. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity[J]. Nature 2001,413(6852):165–171.
[107] Shankaran V, Ikeda H, Bruce AT, et al. IFNg and lymphocytes prevent primary tumour development and shape tumour immunogenicity[J]. Nature 2001,410(6832):1107–1111.
[108] Kusmartsev S, Gabrilovich DI. Role of immature myeloid cells in mechanisms of immune evasion in cancer[J]. Cancer Immunol Immunother 2006,55(3):237–245.
[109] Ghiringhelli F, Puig PE, Roux S, et al. Tumor cells convert immature myeloid dendritic cells into TGF-{h}-secreting cells inducing CD4~+CD25~+ regulatory T cell proliferation[J]. J Exp Med 2005,202(7):919–929.
[110] Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy:moving beyond current vaccines[J]. Nat Med 2004,10(9):909–915.
[111] Hodi FS, Dranoff G. Combinatorial cancer immunotherapy[J]. Adv Immunol 2006,90:341–368.
[112] Gilboa E. DC-based cancer vaccines[J]. J Clin Invest 2007,117:1195–1203.
[113] Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes[J]. Science 2002,298(5594):850–854.
[114] June CH. Principles of adoptive T cell cancer therapy[J]. J Clin Invest 2007,117(5):1204–1212.
[115] Galon J, Costes A, Sanchez-Cabo F, et al. Type,density, and location of immune cells within human colorectal tumors predict clinical outcome[J]. Science 2006,313(5795):1960–1964.
[116] Appay V, Jandus C, Voelter V, et al. New generation vaccine induces effective melanoma-specific CD8~+ T cells in the circulation but not in the tumor site[J]. J Immunol 2006,177(3):1670–1678.
[117] Rosenberg SA, Sherry RM, Morton KE, et al. Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8~+ T cells in patients with melanoma[J]. J Immunol 2005,175(9):6169–6176.
[118] Offringa R. Cancer immunotherapy is more than a numbers game[J]. Science 2006,314(5796):68–69.
[119] Smyth MJ, Cretney E, Kershaw MH, et al. Cytokines in cancer immunity and immunotherapy[J]. Immunol Rev 2004,202:275–293.
[120] Schwartz RN, Stover L, Dutcher J. Managing toxicities of high-dose interleukin-2[J]. Oncology 2002,16(11):11–20.
[121] Kobayashi H, Carrasquillo JA, Paik CH, et al. Differences of biodistribution, pharmacokinetics, and tumor targeting between interleukins 2 and 15[J]. Cancer Res 2000,60(13):3577–3583.
[122] Zamai L, Ponti C, Mirandola P, et al. NK cells and cancer[J]. J Immunol 2007,178:4011–4016.
[123] Andreas Thalheimer. Evaluation of immunological escape mechanisms in a mouse model of colorectal liver metastases[J]. BMC Cancer 2010, 10:82
[2] Norris S, Collins C, Doherty DG, et al. Resident human hepatitis lymphocytes are phenotypically different from circulating lymphocytes[J]. J Hepatol, 1998,28(1):84-96
[3]田志刚.肝脏NK/NKT细胞及其生物学意义.第二军医大学学报[J],2002,23(10):10~57-1060
[4] Doherty DG, O'Farrelly C. Innate and adaptive lymphoid cells In the human liver[J]. Immunol Rev, 2000,174:5-20.
[5] Wiltrout RH. Regulation and antimetastatic functions of liver associated natural killer cells[J]. Immunol Rev, 2000,174:63-76.
[6] Seki S, Habu Y, Kawamura T, et al. The liver as a crucial organ in the first line of host defense:the roles of Kupffer cells,natural killer(NK)cells and NK1.1Ag~+T cells in T helper 1 immune responses[J]. Immunol Rev, 2000,174:35-46
[7] Golden-Mason L, O'Farrelly C. Having it all Stem cells,haematops is and lymphopoiesis in adult human liver[J]. Immunol Cell Biol, 2002,80(1):45-51.
[8] Befeler A S, Di Bisceglie A M. Hepatocellular carcinoma:diagnosis and treatment[J]. Gastroenterology, 2002,122(6):1609-1619.
[9] Verslype C, Van Cutsem E, Dicato M,et a1.The man agement of hepatocellular carcinoma.Current expert opinion and recommendations derived from the 10th World Congress on Gastrointestinal Cancer,Barcelona, 2008. Annals of Oncology, 2009,20(Supplement 7).
[10] Blugartl H, Fong Y. Surgical options in treatment of hepatic metastasis from colorectal cancer[J]. Curt Probl Surg, 1995,32(5): 27
[11] Grabstein KH, Eisenman J, Shanebeck K, et a1. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin 2 receptor[J]. Science, 1994,264(5161): 965-968.
[12] Meazza R, Verdiani S, Biassoni R, et al. Identification of a novel interleukin-15 (IL-15) transcript isoform generated by alternative splicing in human small cell lung cancer cell lines[J]. Oncogene, 1996,12(10): 2187-2192.
[13] Anderson DM, Johnson L, Glaccum MB, et al. Chromosomal assignment and genomic structure of IL-15[J]. Genomics, 1995,25(3): 701-706.
[14] Krause H, Krause H, Jandrig B, et al. Genomic structure and chromosomal localization of the human interleukin 15 gene IL-15[J]. Cytokine, 1996,8(9): 667-674.
[15] Lee YB, Satoh J, Walker DG, et al. Interleukin 15 gene expression in human astrocytes and microglia in culture[J]. Neuroreport, 1996,7(5): 1062-1066.
[16] Giri JG, Anderson DM, Kumaki S, et al. IL-15, a novel T cell growth factor that shares activities andreceptor components with IL-2[J]. J Leukoc Biol, 1995,57(5): 763–766.
[17] Bamford R. N., A. P. Battiata, J. D. Burton, et al. Interleukin (IL) 15/IL-T production by the adult T-cell leukemia cell line HuT-102 is associated with a human T-cell lymphotrophic virus type I region/IL-15 fusion message that lacks many upstream AUGs that normally attenuates IL-15 mRNA translation[J]. Proc. Natl. Acad. Sci. USA 1996,93(7): 2897–2902.
[18] Nishimura H., A. Fujimoto, N. Tamura, et al. A novel autoregulatory mechanism for transcriptional activation of the IL-15 gene by a nonsecretable isoform of IL-15 generated by alternative splicing[J]. FASEB J 2005,19(1): 19–28.
[19] Villinger F., R. Miller, K. Mori, et al. IL-15 is superior to IL-2 in the generation of long-lived antigen specific memory CD4 and CD8 T cells in rhesus macaques[J].Vaccine 2004,22(25-26): 3510–3521.
[20] Cosman D, Kumaki S, Ahdieh M, et al. Interleukin 15 and its receptor[J]. Ciba Found Symp 1995,195:221-229
[21] J.G. Giri, S. Kumaki, M. Ahdieh, et al. Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor[J]. EMBO J 1995,14(15):3654–3663.
[22] D.M. Anderson, S. Kumaki, M. Ahdieh, et al. Tometsko and A. Loomis et al., Functional characterization of the human interleukin-15 receptor alpha chain and close linkage of IL-15RA and IL2RA genes[J]. J Biol Chem 1995,270(50):29862–29869.
[23] T.A. Waldmann. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design[J]. Nat Rev Immunol 2006,6(8):595–601.
[24] S. Bulfone-Paus, E. Bulanova, T. Pohl, et al. Death deflected: IL-15 inhibits TNF-alpha-mediated apoptosis in fibroblasts by TRAF2 recruitment to the IL-15Ralpha chain[J]. FASEB J 1999,13(12):1575–1585.
[25] V. Budagian, E. Bulanova, Z. Orinska, et al. A promiscuous liaison between IL-15 receptor and Axl receptor tyrosine kinase in cell death control[J]. EMBO J 2005,24(24):4260–4270.
[26] E. Bulanova, V. Budagian, T. Pohl, et al. The IL-15R alpha chain signals through association with Syk in human B cells[J]. J Immunol 2001,167(11):6292–6302.
[27] R. Pereno, A. Gaggero, M. Scudeletti, et al. IL-15/IL-15R alpha intracellular trafficking in human cells and protection from apoptosis[J]. Ann N Y Acad Sci 1999,876:236–245.
[28] Lodolce JP, Burkett PR, Boone DL, et al. 2001. T cell-independent interleukin 15Rαsignals are required for bystander proliferation[J]. J. Exp. Med 2001,194(8):1187–1194
[29] Burkett PR, Koka R, Chien M, et al. IL-15Rαexpression on CD8~+ T cells is dispensable for T cell memory[J]. Proc. Natl. Acad. Sci. 2003,100(8):4724–4729
[30] Schluns KS, Klonowski KD, Lefrancois L. Transregulation of memory CD8 T-cell proliferation by IL-15Rαbone marrow-derived cells[J]. Blood 2004,103(3):988–994
[31] Giri JG, Ahdieh M, Eisenman J, et al. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15[J]. EMBO J 1994,13(12):2822–2830.
[32] Dubois S, Mariner J, Waldmann TA, et al. IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells[J]. Immunity 2002,17(5):537–547.
[33] Burkett PR, Koka R, Chien M, et al. Coordinate expression and trans presentation of interleukin (IL)-15Rαand IL-15 supports natural killer cell and memory CD8~+ T cell homeostasis[J]. J. Exp. Med 2004,200(7):825–834
[34] Musso T, Calosso L, Zucca M, et al. Human monocytes constitutively express membrane-bound, biologically active,and interferon-gamma-upregulated interleukin-15[J]. Blood,1999,93 :3531–3539.
[35] Neely GG, Robbins SM, Amankwah EK, et al. Lipopolysaccharide-stimulated or granulocyte-macrophage colonystimulating factor-stimulated monocytes rapidly express biologically active IL-15 on their cell surface independent of new protein synthesis[J]. J Immunol 2001,167(9):5011–5017.
[36] Sandau MM, Schluns KS, Lefrancois L, et al. Cutting edge: transpresentation of IL-15 by bone marrow-derived cells necessitates expression of IL-15 and IL-15Rαby the same cells[J]. J. Immunol 2004,173(11):6537–6541
[37] Koka R, Burkett P, Chien M, et al. Cutting edge: murine dendritic cells require IL-15Rαto prime NK cells[J]. J. Immunol 2004,173(6):3594–3598
[38] Dubois SP, Waldmann TA, Muller JR. Survival adjustment of mature dendritic cells by IL-15[J]. Proc. Natl. Acad. Sci 2005,102(24):8662–8667
[39] Spencer W. Stonier, Kimberly S. Schluns. Trans-presentation: A novel mechanism regulating IL-15 delivery and responses[J]. Immunology Letters 2010,127(2):85–92
[40] Ilangumaran S, Ramanathan S, Ning T, et al. Suppressor of cytokine signaling 1 attenuates IL-15 receptor signaling in CD8~+ thymocytes[J]. Blood 2003,102(12):4115–4122
[41] Kennedy MK, Glaccum M, Brown SN, et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice[J]. J. Exp.Med. 2000,191(5):771–780
[42] Averil Ma, Rima Koka, Patrick Burkett, et al.. Diverse Functions of IL-2, IL-15, and IL-7 in Lymphoid Homeostasis[J]. Annu. Rev. Immunol 2006,24:657–679
[43] Marrack P, Kappler J. Control of T cell viability[J]. Annu. Rev. Immunol 2004,22:765–787
[44] Lodolce JP, Boone DL, Chai S, et al. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation[J]. Immunity 1998,9(5):669–676
[45] Vella AT, Dow S, Potter TA, et al. Cytokine-induced survival of activated T cells in vitro and in vivo[J]. Proc. Natl. Acad. Sci. 1998,95(7):3810–3815
[46] Zhang X, Sun S, Hwang I, et al. Potent and selective stimulation of memory-phenotype CD8~+ T cells in vivo by IL-15[J]. Immunity 1998, 8(5):591–599
[47] Schluns KS, Williams K, Ma A, et al. Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells[J]. J. Immunol 2002,168(10):4827–4831
[48] Becker TC, Wherry EJ, Boone D, et al. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells[J]. J. Exp. Med 2002,195(12):1541–1548
[49] Tagaya Y, Burton JD, Miyamoto Y, et al. Identification of a novel receptor/ signal transduction pathway for IL-15/T in mast cells[J]. EMBO J 1996,15(18):4928–4939
[50] Ku CC, Murakami M, Sakamoto A, et al. Control of homeostasis of CD8~+ memory T cells byopposing cytokines[J]. Science 2000,288(5466):675–678
[51] Goldrath AW, Sivakumar PV, Glaccum M, et al. Cytokine requirements for acute and basal homeostatic proliferation of naive and memory CD8~+ T cells[J]. J. Exp. Med 2002,195(12):1515–1522
[52] Weninger W, Crowley MA, Manjunath N, et al. Migratory properties of naive, effector, and memory CD8~+ T cells[J]. J. Exp. Med 2001,194(7):953–966
[53] Loza MJ, Peters SP, Zangrilli JG, et al. Distinction between IL-13~+ and IFN-γ~+ natural killer cells and regulation of their pool size by IL-4[J]. Eur. J. Immunol 2002, 32(2):413–23
[54] Miller JS, Alley KA, McGlave P. Differentiation of natural killer (NK) cells from human primitive marrow progenitors in a stroma-based long-term culture system: identification of a CD34~+7~+ NK progenitor[J]. Blood 1994,83(9):2594–2601
[55] Mrozek E, Anderson P, Caligiuri MA. Role of interleukin-15 in the development of human CD56~+ natural killer cells from CD34~+ hematopoietic progenitor cells[J]. Blood 1996,87(7):2632–2640
[56] Williams NS, MooreTA, Schatzle JD, et al. Generation of lytic natural killer 1.1, Ly-49? cells from multipotential murine bone marrow progenitors in a stroma-free culture: definition of cytokine requirements and developmental intermediates[J]. J. Exp. Med. 1997,186(9):1609–1614
[57] Maki K, Sunaga S, Komagata Y, et al. Interleukin 7 receptor deficient mice lackγδT cells[J]. Proc. Natl. Acad. Sci. 1996, 93(14):7172–7177
[58] Kundig TM, Schorle H, Bachmann MF, et al. Immune responses in interleukin-2-deficient mice[J]. Science 1993,262(5136):1059–1061
[59] Vosshenrich CA, Ranson T, Samson SI, et al. Roles for common cytokine receptorγ-chain-dependent cytokines in the generation, differentiation, and maturation of NK cell precursors and peripheral NK cells in vivo[J]. J. Immunol. 2005,174(3):1213–1221
[60] Kawamura T, Koka R, Ma A, et al. Differential roles for IL-15Rα-chain in NK cell development and Ly-49 induction[J]. J. Immunol. 2003,171(10):5085–5090
[61] Saleh A, Davies GE, Pascal V, et al. Identification of probabilistic transcriptional switches in the Ly49 gene cluster: a eukaryotic mechanism for selective gene activation[J]. Immunity 2004,21(1):55–66
[62] Arase H, Mocarski ES, Campbell AE, et al. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors[J]. Science 2002,296(5571):1323–1326
[63] Cooper MA,Bush JE, Fehniger TA, et al. In vivo evidence for a dependence on interleukin 15 for survival of natural killer cells[J]. Blood 2002,100(10):3633–3638
[64] Koka R, Burkett PR, Chien M, et al. Interleukin (IL)-15Rα- deficient natural killer cells survive in normal but not IL-15Rα-deficient mice[J]. J. Exp.Med. 2003,197(8):977–984
[65] Minagawa M, Watanabe H, Miyaji C, et al. Enforced expression of Bcl-2 restores the number of NK cells, but does not rescue the impaired development of NKT cells or intraepithelial lymphocytes, in IL-2/IL-15 receptorβ-chain-deficient mice[J]. J. Immunol. 2002,169(8):4153–4160
[66] Nguyen KB, Salazar-Mather TP, Dalod MY, et al. Coordinated and distinct roles for IFN-αβ, IL-12, and IL-15 regulation of NK cell responses to viral infection[J]. J. Immunol. 2002,169(8):4279–4287
[67] Fawaz LM, Sharif-Askari E, Menezes J. Up-regulation of NK cytotoxic activity via IL-15 induction bydifferent viruses: a comparative study[J]. J. Immunol. 1999,163(8):4473–80
[68] Gri G, Chiodoni C, Gallo E, et al. Antitumor effect of interleukin (IL)-12 in the absence of endogenous IFN-γ: a role for intrinsic tumor immunogenicity and IL-15[J]. Cancer Res. 2002,62(15):4390–4397
[69] Comes A, Di Carlo E, Musiani P, et al. IFN-γ-independent synergistic effects of IL-12 and IL-15 induce anti-tumor immune responses in syngeneic mice[J]. Eur. J. Immunol. 2002,32(7):1914–1923
[70] Biber JL, Jabbour S, Parihar R, et al. Administration of two macrophage-derived interferon-γ-inducing factors (IL-12 and IL-15) induces a lethal systemic inflammatory response in mice that is dependent on natural killer cells but does not require interferon-γ[J]. Cell. Immunol. 2002,216(1-2):31–42
[71] Gerosa F, Baldani-Guerra B, Nisii C, et al. Reciprocal activating interaction between natural killer cells and dendritic cells[J]. J. Exp. Med. 2002,195(3):327–333
[72] Fernandez NC, Lozier A, Flament C, et al. Dendritic cells directly triggerNKcell functions: cross-talk relevant in innate anti-tumor immune responses in vivo[J]. Nat. Med. 1999,5(4):405–411
[73] Ferlazzo G, Tsang ML, Moretta L, et al. Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells[J]. J. Exp. Med. 2002,195(3):343–351
[74] Piccioli D, Sbrana S, Melandri E, et al. Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells[J]. J. Exp. Med. 2002,195(3):335–341
[75] Andrews DM, Scalzo AA, Yokoyama WM, et al. Functional interactions between dendritic cells and NK cells during viral infection[J]. Nat. Immunol. 2003,4(2):175–181
[76] Ferrari-Lacraz S.E. Zanelli, M. Neuberg, et al. Targeting IL-15 receptor-bearing cells with an antagonist mutant IL-15/Fc protein prevents disease development and progression in murine collagen-induced arthritis[J]. J. Immunol. 2004,173(9): 5818–5826.
[77] Ruchatz H., B. P. Leung, X. Q. Wei, et al. Soluble IL-15 receptorα-chain administration prevents murine collagen-induced arthritis: a role for IL-15 in development of antigen-induced immunopathology[J]. J. Immunol. 1998,160(11): 5654–5660.
[78] Smith X. G., E. M. Bolton, H. Ruchatz, et al. Selective blockade of IL-15 by soluble IL-15 receptorα-chain enhances cardiac allograft survival[J]. J. Immunol. 2000,165(6): 3444–3450.
[79] Khan I. A., L. H. Kasper. IL-15 augments CD8 T cell-mediatedimmunity against Toxoplasma gondii infection in mice[J]. J. Immunol. 1996,157(5):2103–2108.
[80] Tsunobuchi H., H. Nishimura, F. Goshima, et al. A protective role of interleukin-15 in a mouse model for systemic infection with herpes simplex virus[J].Virology 2000,275(1): 57–66.
[81] Maeurer M. J., P. Trinder, G. Hommel, et al. Interleukin-7 or interleukin-15 enhances survival of Mycobacterium tuberculosis-infected mice[J]. Infect. Immun. 2000,68(5): 2962–2970.
[82] Umemura M., H. Nishimura, K. Hirose, et al. Overexpression of IL-15 in vivo enhances protection against Mycobacterium bovis bacillus Calmette-Guerin infection via augmentation of NK and T cytotoxic 1 responses[J]. J. Immunol. 2000,167(2): 946–956.
[83] Rubinstein M. P., A. N. Kadima, M. L. Salem, et al. Systemic administration of IL-15 augments theantigenspecific primary CD8 T cell response following vaccination with peptide-pulsed dendritic cells[J]. J. Immunol. 2002,169(9): 4928–4935.
[84] Oh S., J. A. Berzofsky, D. S. Burke, et al. Coadministration of HIV vaccine vectors with vaccinia viruses expressing IL-15 but not IL-2 induces long-lasting cellular immunity[J]. Proc. Natl. Acad. Sci. 2003,100(6): 3392–3397.
[85] Hiromatsu T., T. Yajima, T. Matsuguchi, et al. Overexpression of interleukin-15 protects against Escherichia coli-induced shock accompanied by inhibition of tumor necrosis factor-α-induced apoptosis[J]. J. Infect. Dis. 2003,187(9): 1442–1451.
[86] Toka F. N., B. T. Rouse. Mucosal application of plasmid-encoded IL-15 sustains a highly protective anti-Herpes simplex virus immunity[J]. J. Leukocyte Biol. 2005,78(1): 178–186.
[87] Melchionda F., T. J. Fry, M. J. Milliron, et al. Adjuvant IL-7 or IL-15 overcomes immunodominance and improves survival of the CD8 memory cell pool[J]. J. Clin. Invest. 2005,115(5): 1177–1187.
[88]Bamford R. N., A. P. DeFilippis, N. Azimi, et al. The 5 untranslated region, signal peptide, and the coding sequence of the carboxyl terminus of IL-15 participate in its multifaceted translational control[J]. J. Immunol. 1998,160(9): 4418–4426.
[89] Mastroianni C. M., G. d’Ettorre, G. Forcina, et al. Interleukin-15 enhances neutrophil functional activity in patients with human immunodeficiency virus infection[J]. Blood 2000,96(5): 1979–1984.
[90] Chitnis V., R. Pahwa, S. Pahwa . Determinants of HIV-specific CD8 T-cell responses in HIV-infected pediatric patients and enhancement of HIVgag-specific responses with exogenous IL-15[J]. Clin. Immunol. 2003,107(1): 36–45.
[91] Mueller Y. M., P. M. Bojczuk, E. S. Halstead, et al. IL-15 enhances survival and function of HIV-specific CD8 T cells[J]. Blood 2003,101(3): 1024–1029.
[92] Castelli J., E. K. Thomas, M. Gilliet, et al. Mature dendritic cells can enhance CD8 cell noncytotoxic anti-HIV responses: the role of IL-15[J]. Blood 2004,103(7): 2699–2704.
[93] Lum J. J., D. J. Schnepple, Z. Nie, et al. Differential effects of interleukin-7 and interleukin-15 on NK cell anti-human immunodeficiency virus activity[J]. J. Virol. 2004,78(11): 6033–6042.
[94] Forcina G., G. d’Ettorre, C. M. Mastroianni, et al. Interleukin-15 modulates interferon-γandβ-chemokine production in patients with HIV infection: implications for immune-based therapy[J]. Cytokine 2004,25(6): 283–290.
[95] Alpdogan O., J. M. Eng, S. J. Muriglan, et al. Interleukin-15 enhances immune reconstitution after allogenic bone marrow transplantation[J]. Blood 2005,105(2): 865–873.
[96] Chapoval A. I., J. A. Fuller, S. G. Kremlev, et al. Combination chemotherapy and IL-15 administration induce permanent tumor regression in a mouse lung tumor model: NK and T cell-mediated effects antagonized by B cells[J]. J. Immunol. 1998,161(12): 6977–6984.
[97] Wysocka M., B. M. Benoit, S. Newton, et al. Enhancement of the host immune responses in cutaneous T-cell lymphoma by CpG oligodeoxynucleotides and IL-15[J]. Blood 2004,104(13):4142–4149.
[98] Klebanoff C. A., S. E. Finkelstein, D. R. Surman, et al. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8 T cells[J].Proc. Natl. Acad. Sci. 2004, 101(7): 1969–1974.
[99] Teague RM, Sather BD, Sacks JA, et al. Interleukin-15 rescues tolerant CD8~+ T cells for use in adoptive immunotherapy of established tumors[J]. Nat Med 2006,12(3):335–41.
[100] Evans R, Fuller JA, Christianson G, et al. IL-15 mediates anti-tumor effects after cyclophosphamide injection of tumor-bearing mice and enhances adoptive immunotherapy: the potential role of NK cell subpopulations[J]. Cell Immunol 1997,179(1):66–73.
[101] Stoklasek TA, Schluns KS, Lefrancois L. Combined IL-15/IL-15Ra immunotherapy maximizes IL-15 activity in vivo[J]. J Immunol 2006,177(9):6072–6080.
[102] Shannon J. Turley. Interleukin-15/Interleukin-15RA Complexes Promote Destruction of Established Tumors by Reviving Tumor-Resident CD8 T Cells[J]. Cancer Res 2008,68(8): 2972-2983
[103] Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection and immunosubversion[J]. Nat Rev Immunol 2006,6(10):715–727.
[104] Pardoll D. Does the immune system see tumors as foreign or self[J]? Annu Rev Immunol 2003,21:807–839.
[105] Street SE, Hayakawa Y, Zhan Y, et al. Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and gy T cells[J]. J Exp Med 2004,199(6):879–884.
[106] Diefenbach A, Jensen ER, Jamieson AM, et al. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity[J]. Nature 2001,413(6852):165–171.
[107] Shankaran V, Ikeda H, Bruce AT, et al. IFNg and lymphocytes prevent primary tumour development and shape tumour immunogenicity[J]. Nature 2001,410(6832):1107–1111.
[108] Kusmartsev S, Gabrilovich DI. Role of immature myeloid cells in mechanisms of immune evasion in cancer[J]. Cancer Immunol Immunother 2006,55(3):237–245.
[109] Ghiringhelli F, Puig PE, Roux S, et al. Tumor cells convert immature myeloid dendritic cells into TGF-{h}-secreting cells inducing CD4~+CD25~+ regulatory T cell proliferation[J]. J Exp Med 2005,202(7):919–929.
[110] Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy:moving beyond current vaccines[J]. Nat Med 2004,10(9):909–915.
[111] Hodi FS, Dranoff G. Combinatorial cancer immunotherapy[J]. Adv Immunol 2006,90:341–368.
[112] Gilboa E. DC-based cancer vaccines[J]. J Clin Invest 2007,117:1195–1203.
[113] Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes[J]. Science 2002,298(5594):850–854.
[114] June CH. Principles of adoptive T cell cancer therapy[J]. J Clin Invest 2007,117(5):1204–1212.
[115] Galon J, Costes A, Sanchez-Cabo F, et al. Type,density, and location of immune cells within human colorectal tumors predict clinical outcome[J]. Science 2006,313(5795):1960–1964.
[116] Appay V, Jandus C, Voelter V, et al. New generation vaccine induces effective melanoma-specific CD8~+ T cells in the circulation but not in the tumor site[J]. J Immunol 2006,177(3):1670–1678.
[117] Rosenberg SA, Sherry RM, Morton KE, et al. Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8~+ T cells in patients with melanoma[J]. J Immunol 2005,175(9):6169–6176.
[118] Offringa R. Cancer immunotherapy is more than a numbers game[J]. Science 2006,314(5796):68–69.
[119] Smyth MJ, Cretney E, Kershaw MH, et al. Cytokines in cancer immunity and immunotherapy[J]. Immunol Rev 2004,202:275–293.
[120] Schwartz RN, Stover L, Dutcher J. Managing toxicities of high-dose interleukin-2[J]. Oncology 2002,16(11):11–20.
[121] Kobayashi H, Carrasquillo JA, Paik CH, et al. Differences of biodistribution, pharmacokinetics, and tumor targeting between interleukins 2 and 15[J]. Cancer Res 2000,60(13):3577–3583.
[122] Zamai L, Ponti C, Mirandola P, et al. NK cells and cancer[J]. J Immunol 2007,178:4011–4016.
[123] Andreas Thalheimer. Evaluation of immunological escape mechanisms in a mouse model of colorectal liver metastases[J]. BMC Cancer 2010, 10:82