摘要
肝脏的免疫系统别具特色。这不仅因为双重血供使肝脏直接暴露于胃肠道来源的免疫刺激物中,更体现在肝脏免疫细胞的独特组成上。肝窦特殊的结构有利于选择性驻留循环血液中的某些免疫细胞。同时,肝脏的自身造血作用也可能参与改变肝脏免疫细胞的组成。在个体发育的过程中,胚胎肝脏是造血发生的场所之一。虽然出生后造血干细胞会由胎肝转移到骨髓,但是资料显示,成年肝脏仍然具有造血功能。因此,成年肝脏独立于骨髓的造血作用如何影响肝脏免疫细胞的构成是值得探索的科学问题。
肝脏中天然免疫系统处于优势状态,除了存在大量具有吞噬功能的细胞外,肝脏NK细胞和NKT细胞的比例也远远高于全身其它脏器。天然免疫细胞在肝脏富集的机制,以及它们与其它脏器细胞的差别,都引起了学界广泛的关注。肝脏中NK细胞的表型与其他脏器存在明显不同。据报道,肝脏含有大量DX5-表型不成熟的NK细胞。尽管分泌细胞因子的能力和部分细胞毒作用弱于经典DX5+NK细胞,它们可以通过TRAIL相关的方式起杀伤作用。此外,在半抗原介导的过敏性皮炎和部分病毒感染模型中,记忆NK细胞特异性驻留于肝脏。这些现象都表明肝脏NK细胞具有与经典NK细胞不同的特性,暗示着肝脏中DX5NK细胞可能并非处于NK细胞发育的不成熟阶段,而是区别于骨髓发育的NK细胞的另一个亚群。
针对以上切入点,本项研究工作分为两大部分:
I.成年肝脏造血免疫系统发育分化的研究
1.成年肝脏中含有造血干细胞
通过流式检测小鼠肝脏单个核细胞,可以发现成年肝脏中存在造血干细胞表型的细胞。转输肝脏单个核细胞给致死照射后的小鼠,也可以避免小鼠死亡。因此成年肝脏确实具有造血能力。2.肝脏单个核细胞转输重建T细胞为主的免疫系统
肝脏单个核细胞转输后,受者体内髓系系统和淋巴系统都逐渐恢复,但恢复速度比骨髓转输要慢。特别有趣的是,在肝脏单个核细胞转输早期,受者体内重建出以T细胞为主的免疫系统,B细胞和NK细胞比例极低,而骨髓重建的受体中是以B细胞为主的免疫系统。
3.肝脏造血前体细胞具有与骨髓细胞类似的淋巴细胞生成能力
纯化肝脏造血前体细胞转输,证实了肝脏造血前体细胞确实具有与骨髓造血干细胞类似的淋巴细胞生成能力。与肝脏单个核细胞转输的结果不同,肝脏造血前体细胞先重建出B细胞而后再产生T细胞。
4.肝脏成熟T细胞参与受体免疫系统的重建
通过纯化肝脏成熟的T细胞转输,我们发现肝脏T细胞在受者中优先向肝脏归巢,并且能长期存活,维持稳定的细胞群体。此外,转输后扩增的T细胞主要为具记忆表型的CD8T细胞。结论I:成年肝脏中的造血前体细胞以及部分成熟的T细胞都能够产生并维持特定的淋巴细胞群体。肝脏造血前体细胞具有与骨髓造血干细胞类似的T、B细胞生成能力,但两者生成NK细胞的能力差别较大。肝脏驻留的记忆性CD8T细胞在转输后会在受者中大量扩增并优先向肝脏归巢。
Ⅱ.肝脏特有NK细胞亚群的研究
1.肝脏中存在特有NK细胞群体
DX5-NK细胞约占肝脏NK细胞一半左右,而在其它脏器中比例很低。肝脏DX5-NK细胞与骨髓中不成熟的NK细胞存在表型上的差别。利用转输实验,我们也证实了这群细胞能稳定维持群体,不向DX5+NK细胞转化。因此它们是区别于经典NK细胞的特殊亚群,而非不成熟NK细胞。此外,基因芯片结果筛选出CD49a可以作为该亚群的特有标志。
2.肝脏特有NK细胞具有介导记忆反应的能力
在半抗原诱导的过敏性皮炎模型中,我们发现致敏后小鼠肝脏CD49a+DX5-NK细胞可以向未经处理的naive小鼠传递抗原特异的免疫记忆,而CD49a-DX5+NK细胞不能。
3.肝脏特有NK细胞驻留于肝脏并在肝脏局部获得记忆功能
通过转输实验,我们证明了肝脏中驻留的CD49a+DX5-NK细胞天生就具有产生免疫记忆的潜能,该种能力是经典的CD49a-DX5+NK细胞所不具备的。利用FITC作为致敏剂追踪半抗原在体内的分布,可以看到半抗原会被肝实质细胞摄入,同时也观察到荷载半抗原的DC和单核细胞停留在肝脏中,为NK细胞在肝脏局部产生免疫记忆提供了物质基础。
4.肝脏特有NK细胞的发育不依赖于骨髓
骨髓转输能够迅速补充受者体内CD49a-DX5+NK细胞,却不能有效重建肝脏特有CD49a+DX5-NK细胞亚群,提示两者具有不同的发育路径。肝脏造血前体细胞转输实验证实其具有向肝脏特有NK细胞分化的能力。
结论Ⅱ:区别其他脏器,肝脏中存在一群特有的CD49a+DX5-NK细胞。该群细胞特异性驻留于肝脏,不参与血液循环,在半抗原致敏后能够获得抗原特异性的免疫记忆。此外,肝脏特有NK细胞群体由肝脏中的前体细胞分化而来,其发育不依赖于骨髓。
Liver is a unique immunological site, to which dual blood supply brings immune stimulants from gastrointestinal tract, and features by complex repertoires of immune cells capable of effective defense. The structural organization of sinusoids may selectively retain immune cells from circulating blood. Meanwhile, hematopoiesis of adult liver also probably influences the inclusion of hepatic immune system. Fetal liver is one of the hematopoietic places during ontogeny. Though HSCs is generally considered to migrate from fetal liver to BM, the hematopoietic capacity of liver is still found in adults. Thus, the contribution of liver hematopoiesis to liver immune system is of great interest.
The liver is an organ with predominant innate immunity. Besides large population of cells with phagocytosis, NK and NKT cells are in high frequency comparing liver with other organs. The mechanism underlying innate immune domination as well as the different between innate cells in liver and other organs attracts many attentions. Different phenotypes were described in liver NK cells and NK cells in other organs. It has been reported that nearly half of liver NK cells possessed DX5" immature profile, with a weaker secretion of cytokines and cytotoxicity than DX5+classical NK cells, but could kill target cells by TRAIL related pathway. Moreover, memory NK cells in hapten induced contact hypersensitivity and some virus infections were liver resident, implying liver DX5" NK cells might be another NK cell subset rather than a stage during NK cell development.
In view of the above point, this study contains the following two aspects:
I. Liver lymphopoiesis in adult mice
1. Hematopoietic progenitors existed in adult liver.
We analyzed the surface marker on liver mononuclear cells (MNCs) and found cells with the phenotypes of hematopoietic progenitors (HPCs) in them. Further study showed that liver MNCs transfer could rescue lethally irradiated mice, demonstrating hematopoietic capacity of adult liver.
2. Liver MNCs transfer rebuilt immune system predominated by T cells.
Myeloid and lymphoid lineages were slowly rebuilt after liver MNCs transfer. Interestingly, CD3+CD19-T cells were major population in recipients3weeks after liver MNCs transfer, while CD3-CD19+B cells were major population in BM transfer groups.
3. Liver MNCs contained HPCs functionally similar to BM cells.
Purified liver HPCs similarly reconstituted T and B cells as BM cells. Contrast to T cell predominance after liver MNCs transfer, liver HPCs regenerated T cells later than B cells.
4. Liver MNCs contained liver-resident memory CD8+T cells.
Hepatic mature T cells recruited to the liver after transfer. They proliferated and maintained population for long time. Most of them were CD8T cells with memory phenotypes.
Conclusion Ⅰ:Adult liver contained both HPCs and T cells with lymphopoietic capacity. T and B cells were similarly reconstituted by HPCs in the liver and BM, but NK cell recovery was quite different. Liver resident memory CD8T cells also rapidly proliferated and long-lived after transfer with liver specific retention.
Ⅱ. The features of liver unique NK cells
1. Liver contained a unique NK cell subset.
Nearly half of hepatic NK1.1+NK cells were DX5-NK cells, which were rare in other organs and phenotypically distinct from BM immature NK cells. They maintained DX5-phenotype and did not convert to DX5+NK cells after adoptive transfer, implying they were NK cell subset different from classical NK cells rather than immature NK cells. Besides, we found CD49a was a specific marker for them by genechip.
2. Hepatic unique NK cells conferred CHS responses.
In hapten induced contact hypersensitivity (CHS), CD49a+DX5-NK cells isolated from sensitized mice liver delivered antigen specific memory to naive mice, while CD49a DX5+NK cells could not.
3. Memory NK cells were liver resident and priming in the liver.
Liver unique NK cells naturally possessed memory capacity. They resided in the liver and acquired memory ability after hapten sensitization. We traced hapten delivery by FITC, and found hepatocytes could absorb haptens after sensitization. Monocytes and DCs also took part in this process. Thus, liver might be a site where naive NK cells were primed.
4. Liver-resident HPCs differentiated into CD49a+DX5-NK cells.
Very few DX5-NK cells were detected in the livers of BM transplanted mice, suggesting that DX5-NK cells were not predominantly derived from BM. We transferred purified hepatic precursors and found they could give rise to liver unique NK cells.
Conclusion Ⅱ:We identified a unique NK cell subset in the liver characterized by the CD49a+DX5-phenotype. This subset possessed memory potential and conferred hapten-specific CHS responses upon hapten challenge. Importantly, CD49a+DX5-NK cells were liver resident and appeared to originate from hepatic HPCs but not from the BM.
引文
Abdul-Careem, M.F., Lee, A.J., Pek, E.A., Gill, N., Gillgrass, A.E., Chew, M.V., Reid, S., and Ashkar, A.A. (2012). Genital HSV-2 infection induces short-term NK cell memory. PloS one 7,e32821.
Adams, D.H., and Eksteen, B. (2006). Aberrant homing of mucosal T cells and extra-intestinal manifestations of inflammatory bowel disease. Nature reviews. Immunology 6,244-251.
Ahmed, R., and Gray, D. (1996). Immunological memory and protective immunity:understanding their relation. Science 272,54-60.
Alexander, S.I., Smith, N., Hu, M., Verran, D., Shun, A., Dorney, S., Smith, A., Webster, B., Shaw, P.J., Lammi, A., and Stormon, M.O. (2008). Chimerism and tolerance in a recipient of a deceased-donor liver transplant. The New England journal of medicine 358,369-374.
Andre, P., Castriconi, R., Espeli, M., Anfossi, N., Juarez, T., Hue, S., Conway, H., Romagne, F., Dondero, A., Nanni, M., et al. (2004). Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors. European journal of immunology 34, 961-971.
Antoine, C., Muller, S., Cant, A., Cavazzana-Calvo, M., Veys, P., Vossen, J., Fasth, A., Heilmann, C., Wulffraat, N., Seger, R., et al. (2003). Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies:report of the European experience 1968-99. Lancet 361,553-560.
Arase, H., Mocarski, E.S., Campbell, A.E., Hill, A.B., and Lanier, L.L. (2002). Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296,1323-1326.
Asakura, A., and Rudnicki, M.A. (2002). Side population cells from diverse adult tissues are capable of in vitro hematopoietic differentiation. Experimental hematology 30,1339-1345.
Aversa, F., Martelli, M.M., and Reisner, Y. (1997). Use of stem cells from mismatched related donors. Current opinion in hematology 4,419-422.
Bertolino, P., Trescol-Biemont, M.C., and Rabourdin-Combe, C. (1998). Hepatocytes induce functional activation of naive CD8+T lymphocytes but fail to promote survival. European journal of immunology 28,221-236.
Bertrand, J.Y., Giroux, S., Golub, R., Klaine, M., Jalil, A., Boucontet, L., Godin, I., and Cumano, A. (2005). Characterization of purified intraembryonic hematopoietic stem cells as a tool to define their site of origin. Proceedings of the National Academy of Sciences of the United States of America 102,134-139.
Biassoni, R. (2008). Natural killer cell receptors. Advances in experimental medicine and biology 640,35-52.
Bilezikci, B., Sahin, F., Uyar, P., Yilmaz, Z., Demirhan, B., Turan, M., Arat, Z., and Haberal, M. (2006). Frequency of recipient-derived chimerism and relationship with acute rejection and HLA tissue typing in transplanted livers. Transplantation proceedings 38,598-601.
Biron, C.A. (2010). More things in heaven and earth:defining innate and adaptive immunity. Nature immunology 11,1080-1082.
Brandstadter, J.D., and Yang, Y. (2011). Natural killer cell responses to viral infection. Journal of innate immunity 3,274-279.
Brauner, H., Elemans, M., Lemos, S., Broberger, C., Holmberg, D., Flodstrom-Tullberg, M., Karre, K., and Hoglund, P. (2010). Distinct phenotype and function of NK cells in the pancreas of nonobese diabetic mice. Journal of immunology 184,2272-2280.
Burgio, V.L., Ballardini, G.s Artini, M., Caratozzolo, M., Bianchi, F.B., and Levrero, M. (1998). Expression of co-stimulatory molecules by Kupffer cells in chronic hepatitis of hepatitis C virus etiology. Hepatology 27,1600-1606.
Calne, R.Y., Sells, R.A., Pena, J.R., Davis, D.R., Millard, P.R., Herbertson, B.M., Binns, R.M., and Davies, D.A. (1969). Induction of immunological tolerance by porcine liver allografts. Nature 223,472-476.
Carotta, S., Pang, S.H., Nutt, S.L., and Belz, G.T. (2011). Identification of the earliest NK-cell precursor in the mouse BM. Blood 117,5449-5452.
Cedar, H., and Bergman, Y. (2011). Epigenetics of haematopoietic cell development. Nature reviews. Immunology 11,478-488.
Chiossone, L., Chaix, J., Fuseri, N., Roth, C., Vivier, E., and Walzer, T. (2009). Maturation of mouse NK cells is a 4-stage developmental program. Blood 113,5488-5496.
Chung, B., Barbara-Burnham, L., Barsky, L., and Weinberg, K. (2001). Radiosensitivity of thymic interleukin-7 production and thymopoiesis after bone marrow transplantation. Blood 98, 1601-1606.
Collins, R.H., Jr., Anastasi, J., Terstappen, L.W., Nikaein, A., Feng, J., Fay, J.W., Klintmalm, G, and Stone, M.J. (1993). Brief report:donor-derived long-term multilineage hematopoiesis in a liver-transplant recipient. The New England journal of medicine 328,762-765.
Colucci, F., Samson, S.I., DeKoter, R.P., Lantz, O., Singh, H., and Di Santo, J.P. (2001). Differential requirement for the transcription factor PU.l in the generation of natural killer cells versus B and T cells. Blood 97,2625-2632.
Cooper, M.A., Elliott, J.M., Keyel, P.A., Yang, L., Carrero, J.A., and Yokoyama, W.M. (2009). Cytokine-induced memory-like natural killer cells. Proceedings of the National Academy of Sciences of the United States of America 106,1915-1919.
Cooper, M.A., Fehniger, T.A., and Caligiuri, M.A. (2001). The biology of human natural killer-cell subsets. Trends in immunology 22,633-640.
Costa, G, Kouskoff, V., and Lacaud, G (2012). Origin of blood cells and HSC production in the embryo. Trends in immunology 33,215-223.
Crispe, I.N. (2001). Isolation of mouse intrahepatic lymphocytes. Current protocols in immunology/edited by John E. Coligan... [et al.] Chapter 3, Unit 321.
Crispe, I.N. (2009). The liver as a lymphoid organ. Annual review of immunology 27,147-163.
Crispe, I.N., Dao, T., Klugewitz, K., Mehal, W.Z., and Metz, D.P. (2000). The liver as a site of T-cell apoptosis:graveyard, or killing field? Immunological reviews 174,47-62.
Crosbie, O.M., Reynolds, M., McEntee, G, Traynor, O., Hegarty, J.E., and O'Farrelly, C. (1999). In vitro evidence for the presence of hematopoietic stem cells in the adult human liver. Hepatology 29,1193-1198.
Cruz-Guilloty, F., Pipkin, M.E., Djuretic, I.M., Levanon, D., Lotem, J., Lichtenheld, M.G, Groner, Y., and Rao, A. (2009). Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs. The Journal of experimental medicine 206,51-59.
Cui, K., Zang, C., Roh, T.Y., Schones, D.E., Childs, R.W., Peng, W., and Zhao, K. (2009). Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation. Cell stem cell 4,80-93.
Cumano, A., and Godin, I. (2007). Ontogeny of the hematopoietic system. Annual review of immunology 25,745-785.
Demetris, A.J., Murase, N., Fujisaki, S., Fung, J.J., Rao, A.S., and Starzl, T.E. (1993). Hematolymphoid cell trafficking, microchimerism, and GVH reactions after liver, bone marrow, and heart transplantation. Transplantation proceedings 25,3337-3344.
Di Rosa, F., and Pabst, R. (2005). The bone marrow:a nest for migratory memory T cells. Trends in immunology 26,360-366.
Di Santo, J.P. (2006). Natural killer cell developmental pathways:a question of balance. Annual review of immunology 24,257-286.
Di Santo, J.P., and Vosshenrich, C.A. (2006). Bone marrow versus thymic pathways of natural killer cell development. Immunological reviews 214,35-46.
Dieterlen-Lievre, F. (1975). On the origin of haemopoietic stem cells in the avian embryo:an experimental approach. Journal of embryology and experimental morphology 33,607-619.
Doherty, D.G, and O'Farrelly, C. (2000). Innate and adaptive lymphoid cells in the human liver. Immunological reviews 174,5-20.
Dokun, A.O., Chu, D.T., Yang, L., Bendelac, A.S., and Yokoyama, W.M. (2001). Analysis of in situ NK cell responses during viral infection. Journal of immunology 167,5286-5293.
Douek, D.C., Vescio, R.A., Betts, M.R., Brenchley, J.M., Hill, B.J., Zhang, L., Berenson, J.R., Collins, R.H., and Koup, R.A. (2000). Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet 355, 1875-1881.
Emambokus, N.R., and Frampton, J. (2003). The glycoprotein IIb molecule is expressed on early murine hematopoietic progenitors and regulates their numbers in sites of hematopoiesis. Immunity 19,33-45.
Emoto, M., and Kaufmann, S.H. (2003). Liver NKT cells:an account of heterogeneity. Trends in immunology 24,364-369.
Fathman, J.W., Bhattacharya, D., Inlay, M.A., Seita, J., Karsunky, H., and Weissman, I.L. (2011). Identification of the earliest natural killer cell-committed progenitor in murine bone marrow. Blood 118,5439-5447.
Foley, B., Cooley, S., Verneris, M.R., Curtsinger, J., Luo, X., Waller, E.K., Anasetti, C., Weisdorf, D., and Miller, J.S. (2012). Human cytomegalovirus (CMV)-induced memory-like NKG2C(+) NK cells are transplantable and expand in vivo in response to recipient CMV antigen. Journal of immunology 189,5082-5088.
Fraser, R., Dobbs, B.R., and Rogers, G.W. (1995). Lipoproteins and the liver sieve:the role of the fenestrated sinusoidal endothelium in lipoprotein metabolism, atherosclerosis, and cirrhosis. Hepatology 21,863-874.
Freud, A.G, Becknell, B., Roychowdhury, S., Mao, H.C., Ferketich, A.K., Nuovo, GJ., Hughes, T.L., Marburger, T.B., Sung, J., Baiocchi, R.A., et al. (2005). A human CD34(+) subset resides in lymph nodes and differentiates into CD56bright natural killer cells. Immunity 22, 295-304.
Freud, A.G, Yokohama, A., Becknell, B., Lee, M.T., Mao, H.C., Ferketich, A.K., and Caligiuri, M.A. (2006). Evidence for discrete stages of human natural killer cell differentiation in vivo. The Journal of experimental medicine 203,1033-1043.
Friedman, S.L. (2008). Hepatic stellate cells:protean, multifunctional, and enigmatic cells of the liver. Physiological reviews 88,125-172.
Galloway, J.L., and Zon, L.I. (2003). Ontogeny of hematopoiesis:examining the emergence of hematopoietic cells in the vertebrate embryo. Current topics in developmental biology 53, 139-158.
Gao, B., Jeong, W.I., and Tian, Z. (2008). Liver:An organ with predominant innate immunity. Hepatology 47,729-736.
Gascoyne, D.M., Long, E., Veiga-Fernandes, H., de Boer, J., Williams,0., Seddon, B., Coles, M., Kioussis, D., and Brady, H.J. (2009). The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development. Nature immunology 10,1118-1124.
Gilfillan, S., Ho, E.L., Cella, M., Yokoyama, W.M., and Colonna, M. (2002). NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation. Nature immunology 3, 1150-1155.
Gillard, GO., Bivas-Benita, M., Hovav, A.H., Grandpre, L.E., Panas, M.W., Seaman, M.S., Haynes, B.F., and Letvin, N.L. (2011). Thyl+ NK [corrected] cells from vaccinia virus-primed mice confer protection against vaccinia virus challenge in the absence of adaptive lymphocytes. PLoS pathogens 7, e1002141.
Godin, I., and Cumano, A. (2002). The hare and the tortoise:an embryonic haematopoietic race. Nature reviews. Immunology 2,593-604.
Godin, I., Dieterlen-Lievre, F., and Cumano, A. (1995). Emergence of multipotent hemopoietic cells in the yolk sac and paraaortic splanchnopleura in mouse embryos, beginning at 8.5 days postcoitus. Proceedings of the National Academy of Sciences of the United States of America 92,773-777.
Godin, I., Garcia-Porrero, J.A., Dieterlen-Lievre, F., and Cumano, A. (1999). Stem cell emergence and hemopoietic activity are incompatible in mouse intraembryonic sites. The Journal of experimental medicine 190,43-52.
Gordon, S.M., Chaix, J., Rupp, L.J., Wu, J., Madera, S., Sun, J.C., Lindsten, T., and Reiner, S.L. (2012). The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity 36,55-67.
Gothert, J.R., Gustin, S.E., Hall, M.A., Green, A.R., Gottgens, B., Izon, D.J., and Begley, C.G. (2005). In vivo fate-tracing studies using the Scl stem cell enhancer:embryonic hematopoietic stem cells significantly contribute to adult hematopoiesis. Blood 105, 2724-2732.
Grenningloh, R., Tai, T.S., Frahm, N., Hongo, T.C., Chicoine, A.T., Brander, G., Kaufmann, D.E., and Ho, I.C. (2011). Ets-1 maintains IL-7 receptor expression in peripheral T cells. Journal of immunology 186,969-976.
Guidotti, L.G., Rochford, R., Chung, J., Shapiro, M., Purcell, R., and Chisari, F.V. (1999). Viral clearance without destruction of infected cells during acute HBV infection. Science 284, 825-829.
Hao, J., Liu, R., Piao, W., Zhou, Q., Vollmer, T.L., Campagnolo, D.I., Xiang, R., La Cava, A., Van Kaer, L., and Shi, F.D. (2010). Central nervous system (CNS)-resident natural killer cells suppress Th17 responses and CNS autoimmune pathology. The Journal of experimental medicine 207,1907-1921.
Herberman, R.B., Nunn, M.E., and Lavrin, D.H. (1975). Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. I. Distribution of reactivity and specificity. International journal of cancer. Journal international du cancer 16,216-229.
Hiby, S.E., Apps, R., Sharkey, A.M., Farrell, L.E., Gardner, L., Mulder, A., Claas, F.H., Walker, J.J., Redman, C.W., Morgan, L., et al. (2010). Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2. The Journal of clinical investigation 120,4102-4110.
Huntington, N.D., Tabarias, H., Fairfax, K., Brady, J., Hayakawa, Y., Degli-Esposti, M.A., Smyth, M.J., Tarlinton, D.M., and Nutt, S.L. (2007). NK cell maturation and peripheral homeostasis is associated with KLRG1 up-regulation. Journal of immunology 178,4764-4770.
Igarashi, H., Kouro, T., Yokota, T., Comp, P.C., and Kincade, P.W. (2001). Age and stage dependency of estrogen receptor expression by lymphocyte precursors. Proceedings of the National Academy of Sciences of the United States of America 98,15131-15136.
Ishibashi, H., Nakamura, M., Komori, A., Migita, K., and Shimoda, S. (2009). Liver architecture, cell function, and disease. Seminars in immunopathology 31,399-409.
Isogawa, M., Furuichi, Y, and Chisari, F.V. (2005). Oscillating CD8(+) T cell effector functions after antigen recognition in the liver. Immunity 23,53-63.
Ivanovs, A., Rybtsov, S., Welch, L., Anderson, R.A., Turner, M.L., and Medvinsky, A. (2011). Highly potent human hematopoietic stem cells first emerge in the intraembryonic aorta-gonad-mesonephros region. The Journal of experimental medicine 208,2417-2427.
Jinushi, M., Takehara, T., Tatsumi, T., Yamaguchi, S., Sakamori, R., Hiramatsu, N., Kanto, T., Ohkawa, K., and Hayashi, N. (2007). Natural killer cell and hepatic cell interaction via NKG2A leads to dendritic cell-mediated induction of CD4 CD25 T cells with PD-1-dependent regulatory activities. Immunology 120,73-82.
Jo, E.K. (2008). Mycobacterial interaction with innate receptors:TLRs, C-type lectins, and NLRs. Current opinion in infectious diseases 21,279-286.
Kamizono, S., Duncan, GS., Seidel, M.G, Morimoto, A., Hamada, K., Grosveld, G, Akashi, K., Lind, E.F., Haight, J.P., Ohashi, P.S., et al. (2009). Nfil3/E4bp4 is required for the development and maturation of NK cells in vivo. The Journal of experimental medicine 206, 2977-2986.
Kawai, T., and Akira, S. (2008). Toll-like receptor and RIG-I-like receptor signaling. Annals of the New York Academy of Sciences 1143,1-20.
Kiel, M.J., and Morrison, S.J. (2006). Maintaining hematopoietic stem cells in the vascular niche. Immunity 25,862-864.
Kiel, M.J., Radice, G.L., and Morrison, S.J. (2007). Lack of evidence that hematopoietic stem cells depend on N-cadherin-mediated adhesion to osteoblasts for their maintenance. Cell stem cell 1,204-217.
Kiessling, R., Klein, E., and Wigzell, H. (1975). "Natural" killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. European journal of immunology 5,112-117.
Kim, S., Iizuka, K., Kang, H.S., Dokun, A., French, A.R., Greco, S., and Yokoyama, W.M. (2002). In vivo developmental stages in murine natural killer cell maturation. Nature immunology 3, 523-528.
Knolle, P., Schlaak, J., Uhrig, A., Kempf, P., Meyer zum Buschenfelde, K.H., and Gerken, G. (1995). Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. Journal of hepatology 22,226-229.
Knolle, P.A., and Limmer, A. (2001). Neighborhood politics:the immunoregulatory function of organ-resident liver endothelial cells. Trends in immunology 22,432-437.
Knolle, P.A., Schmitt, E., Jin, S., Germann, T., Duchmann, R., Hegenbarth, S., Gerken, G, and Lohse, A.W. (1999). Induction of cytokine production in naive CD4(+) T cells by antigen-presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward Thl cells. Gastroenterology 116,1428-1440.
Kondo, M., Wagers, A.J., Manz, M.G., Prohaska, S.S., Scherer, D.C., Beilhack, G.F., Shizuru, J.A., and Weissman, I.L. (2003). Biology of hematopoietic stem cells and progenitors:implications for clinical application. Annual review of immunology 21,759-806.
Kotton, D.N., Fabian, A.J., and Mulligan, R.C. (2005). A novel stem-cell population in adult liver with potent hematopoietic-reconstitution activity. Blood 106,1574-1580.
Krebs, P., Barnes, M.J., Lampe, K., Whitley, K., Bahjat, K.S., Beutler, B., Janssen, E., and Hoebe, K. (2009). NK-cell-mediated killing of target cells triggers robust antigen-specific T-cell-mediated and humoral responses. Blood 113,6593-6602.
Krueger, P.D., Lassen, M.G, Qiao, H., and Hahn, Y.S. (2011). Regulation of NK cell repertoire and function in the liver. Critical reviews in immunology 31,43-52.
Kudo, S., Matsuno, K., Ezaki, T., and Ogawa, M. (1997). A novel migration pathway for rat dendritic cells from the blood:hepatic sinusoids-lymph translocation. The Journal of experimental medicine 185,777-784.
Kumar, V., Ben-Ezra, J., Bennett, M., and Sonnenfeld, G. (1979). Natural killer cells in mice treated with 89strontium:normal target-binding cell numbers but inability to kill even after interferon administration. Journal of immunology 123,1832-1838.
Kumaravelu, P., Hook, L., Morrison, A.M., Ure, J., Zhao, S., Zuyev, S., Ansell, J., and Medvinsky, A. (2002). Quantitative developmental anatomy of definitive haematopoietic stem cells/long-term repopulating units (HSC/RUs):role of the aorta-gonad-mesonephros (AGM) region and the yolk sac in colonisation of the mouse embryonic liver. Development 129, 4891-4899.
Lalor, P.F., and Adams, D.H. (2002). The liver:a model of organ-specific lymphocyte recruitment. Expert reviews in molecular medicine 4,1-16.
Lanier, L.L. (2005). NK cell recognition. Annual review of immunology 23,225-274.
Lanier, L.L. (2008). Up on the tightrope:natural killer cell activation and inhibition. Nature immunology 9,495-502.
Lassen, M.G, Lukens, J.R., Dolina, J.S., Brown, M.G, and Hahn, Y.S. (2010). Intrahepatic IL-10 maintains NKG2A+Ly49-liver NK cells in a functionally hyporesponsive state. Journal of immunology 184,2693-2701.
Lau, A.H., and Thomson, A.W. (2003). Dendritic cells and immune regulation in the liver. Gut 52, 307-314.
Laurenti, E., and Dick, J.E. (2012). Molecular and functional characterization of early human hematopoiesis. Annals of the New York Academy of Sciences 1266,68-71.
Lee, S.H., and Biron, C.A. (2010). Here today--not gone tomorrow:roles for activating receptors in sustaining NK cells during viral infections. European journal of immunology 40,923-932.
Limmer, A., Ohl, J., Kurts, C., Ljunggren, H.G, Reiss, Y., Groettrup, M., Momburg, F., Arnold, B., and Knolle, P.A. (2000). Efficient presentation of exogenous antigen by liver endothelial cells to CD8+T cells results in antigen-specific T-cell tolerance. Nature medicine 6,1348-1354.
Limmer, A., Ohl, J., Wingender, G, Berg, M., Jungerkes, F., Schumak, B., Djandji, D., Scholz, K., Klevenz, A., Hegenbarth, S., et al. (2005). Cross-presentation of oral antigens by liver sinusoidal endothelial cells leads to CD8 T cell tolerance. European journal of immunology 35,2970-2981.
Lloyd, C.M., Phillips, A.R., Cooper, GJ., and Dunbar, P.R. (2008). Three-colour fluorescence immunohistochemistry reveals the diversity of cells staining for macrophage markers in murine spleen and liver. Journal of immunological methods 334,70-81.
Lohse, A.W., Knolle, P.A., Bilo, K., Uhrig, A., Waldmann, C., Ibe, M., Schmitt, E., Gerken, G, and Meyer Zum Buschenfelde, K.H. (1996). Antigen-presenting function and B7 expression of murine sinusoidal endothelial cells and Kupffer cells. Gastroenterology 110,1175-1181.
Lumsden, A.B., Henderson, J.M., and Kutner, M.H. (1988). Endotoxin levels measured by a chromogenic assay in portal, hepatic and peripheral venous blood in patients with cirrhosis. Hepatology 8,232-236.
Male, V., Nisoli, I., Gascoyne, D.M., and Brady, H.J. (2012). E4BP4:an unexpected player in the immune response. Trends in immunology 33,98-102.
Manz, R.A., Thiel, A., and Radbruch, A. (1997). Lifetime of plasma cells in the bone marrow. Nature 388,133-134.
Martin-Fontecha, A., Thomsen, L.L., Brett, S., Gerard, C., Lipp, M., Lanzavecchia, A., and Sallusto, F. (2004). Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nature immunology 5,1260-1265.
Mathew, P.A., Garni-Wagner, B.A., Land, K., Takashima, A., Stoneman, E., Bennett, M., and Kumar, V. (1993). Cloning and characterization of the 2B4 gene encoding a molecule associated with non-MHC-restricted killing mediated by activated natural killer cells and T cells. Journal of immunology 151,5328-5337.
Matsuno, K., Ezaki, T., Kudo, S., and Uehara, Y. (1996). A life stage of particle-laden rat dendritic cells in vivo:their terminal division, active phagocytosis, and translocation from the liver to the draining lymph. The Journal of experimental medicine 183,1865-1878.
Medvinsky, A., and Dzierzak, E. (1996). Definitive hematopoiesis is autonomously initiated by the AGM region. Cell 86,897-906.
Metcalf, D. (1970). Studies on colony formation in vitro by mouse bone marrow cells. Ⅱ. Action of colony stimulating factor. Journal of cellular physiology 76,89-99.
Milush, J.M., Long, B.R., Snyder-Cappione, J.E., Cappione, A.J.,3rd, York, V.A., Ndhlovu, L.C., Lanier, L.L., Michaelsson, J., and Nixon, D.F. (2009). Functionally distinct subsets of human NK cells, and monocyte/DC-like cells identified by coexpression of CD56, CD7, and CD4. Blood 114,4823-4831.
Min-Oo, G., Kamimura, Y., Hendricks, D.W., Nabekura, T., and Lanier, L.L. (2013). Natural killer cells:walking three paths down memory lane. Trends in immunology.
Moore, M.A., and Metcalf, D. (1970). Ontogeny of the haemopoietic system:yolk sac origin of in vivo and in vitro colony forming cells in the developing mouse embryo. British journal of haematology 18,279-296.
Morgan, B.P., and Gasque, P. (1997). Extrahepatic complement biosynthesis:where, when and why? Clinical and experimental immunology 107,1-7.
Morrison, S.J., Hemmati, H.D., Wandycz, A.M., and Weissman, I.L. (1995). The purification and characterization of fetal liver hematopoietic stem cells. Proceedings of the National Academy of Sciences of the United States of America 92,10302-10306.
Mortensen, E.S., Fenton, K.A., and Rekvig, O.P. (2008). Lupus nephritis:the central role of nucleosomes revealed. The American journal of pathology 172,275-283.
Murakami, J., Shimizu, Y., Kashii, Y., Kato, T., Minemura, M., Okada, K., Nambu, S., Takahara, T., Higuchi, K., Maeda, Y., et al. (1999). Functional B-cell response in intrahepatic lymphoid follicles in chronic hepatitis C. Hepatology 30,143-150.
Naito, M., Hasegawa, G., and Takahashi, K. (1997). Development, differentiation, and maturation of Kupffer cells. Microscopy research and technique 39,350-364.
Nemeth, E., Baird, A.W., and O'Farrelly, C. (2009). Microanatomy of the liver immune system. Seminars in immunopathology 31,333-343.
Ng, I.O., Chan, K.L., Shek, W.H., Lee, J.M., Fong, D.Y., Lo, C.M., and Fan, S.T. (2003). High frequency of chimerism in transplanted livers. Hepatology 38,989-998.
Norris, S., Collins, C., Doherty, D.G., Smith, F., McEntee, G, Traynor, O., Nolan, N., Hegarty, J., and O'Farrelly, C. (1998). Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes. Journal of hepatology 28,84-90.
O'Leary, J.G., Goodarzi, M., Drayton, D.L., and von Andrian, U.H. (2006). T cell-and B cell-independent adaptive immunity mediated by natural killer cells. Nature immunology 7, 507-516.
Obata, K., Mukai, K., Tsujimura, Y., Ishiwata, K., Kawano, Y., Minegishi, Y., Watanabe, N., and Karasuyama, H. (2007). Basophils are essential initiators of a novel type of chronic allergic inflammation. Blood 110,913-920.
Okamoto, Y., Douek, D.C., McFarland, R.D., and Koup, R.A. (2002). Effects of exogenous interleukin-7 on human thymus function. Blood 99,2851-2858.
Orkin, S.H. (2000). Diversification of haematopoietic stem cells to specific lineages. Nature reviews. Genetics 1,57-64.
Orkin, S.H., and Zon, L.I. (2002). Hematopoiesis and stem cells:plasticity versus developmental heterogeneity. Nature immunology 3,323-328.
Orkin, S.H., and Zon, L.I. (2008). Hematopoiesis:an evolving paradigm for stem cell biology. Cell 132,631-644.
Ottaviani, C., Nasorri, F., Bedini, C., de Pita, O., Girolomoni, G., and Cavani, A. (2006). CD56brightCD16(-) NK cells accumulate in psoriatic skin in response to CXCL10 and CCL5 and exacerbate skin inflammation. European journal of immunology 36,118-128.
Paik, Y.H., Schwabe, R.F., Bataller, R., Russo, M.P., Jobin, C., and Brenner, D.A. (2003). Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology 37,1043-1055.
Palis, J., Robertson, S., Kennedy, M., Wall, C., and Keller, G (1999). Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse. Development 126, 5073-5084.
Palm, N.W., and Medzhitov, R. (2009). Pattern recognition receptors and control of adaptive immunity. Immunological reviews 227,221-233.
Passegue, E., Wagers, A.J., Giuriato, S., Anderson, W.C., and Weissman, I.L. (2005). Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. The Journal of experimental medicine 202,1599-1611.
Paust, S., Gill, H.S., Wang, B.Z., Flynn, M.P., Moseman, E.A., Senman, B., Szczepanik, M., Telenti, A., Askenase, P.W., Compans, R.W., and von Andrian, U.H. (2010). Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses. Nature immunology 11,1127-1135.
Paust, S., and von Andrian, U.H. (2011). Natural killer cell memory. Nature immunology 12, 500-508.
Petersen, S.L., Ryder, L.P., Bjork, P., Madsen, H.O., Heilmann, C., Jacobsen, N., Sengelov, H., and Vindelov, L.L. (2003). A comparison of T-, B-and NK-cell reconstitution following conventional or nonmyeloablative conditioning and transplantation with bone marrow or peripheral blood stem cells from human leucocyte antigen identical sibling donors. Bone marrow transplantation 32,65-72.
Purton, L.E., and Scadden, D.T. (2007). Limiting factors in murine hematopoietic stem cell assays. Cell stem cell 1,263-270.
Puzanov, I.J., Bennett, M., and Kumar, V. (1996). IL-15 can substitute for the marrow microenvironment in the differentiation of natural killer cells. Journal of immunology 157, 4282-4285.
Racanelli, V., and Rehermann, B. (2006). The liver as an immunological organ. Hepatology 43, S54-62.
Racanelli, V., Sansonno, D., Piccoli, C., D'Amore, F.P., Tucci, F.A., and Dammacco, F. (2001). Molecular characterization of B cell clonal expansions in the liver of chronically hepatitis C virus-infected patients. Journal of immunology 167,21-29.
Rappaport, A.M., Borowy, Z.J., Lougheed, W.M., and Lotto, W.N. (1954). Subdivision of hexagonal liver lobules into a structural and functional unit; role in hepatic physiology and pathology. The Anatomical record 119,11-33.
Roland, C.R., Walp, L., Stack, R.M., and Flye, M.W. (1994). Outcome of Kupffer cell antigen presentation to a cloned murine Thl lymphocyte depends on the inducibility of nitric oxide synthase by IFN-gamma. Journal of immunology 153,5453-5464.
Romee, R., Schneider, S.E., Leong, J.W., Chase, J.M., Keppel, C.R., Sullivan, R.P., Cooper, M.A., and Fehniger, T.A. (2012). Cytokine activation induces human memory-like NK cells. Blood 120,4751-4760.
Rosen, D.B., Araki, M., Hamerman, J.A., Chen, T., Yamamura, T., and Lanier, L.L. (2004). A Structural basis for the association of DAP 12 with mouse, but not human, NKG2D. Journal of immunology 173,2470-2478.
Rosenberg, E.B., McCoy, J.L., Green, S.S., Donnelly, F.C., Siwarski, D.F., Levine, P.H., and Herberman, R.B. (1974). Destruction of human lymphoid tissue-culture cell lines by human peripheral lymphocytes in 51Cr-release cellular cytotoxicity assays. Journal of the National Cancer Institute 52,345-352.
Rosmaraki, E.E., Douagi, I., Roth, C., Colucci, F., Cumano, A., and Di Santo, J.P. (2001). Identification of committed NK cell progenitors in adult murine bone marrow. European journal of immunology 31,1900-1909.
Roux, E., Dumont-Girard, F., Starobinski, M., Siegrist, C.A., Helg, C., Chapuis, B., and Roosnek, E. (2000). Recovery of immune reactivity after T-cell-depleted bone marrow transplantation depends on thymic activity. Blood 96,2299-2303.
Sakamoto, T., Murase, N., Ye, Q., Starzl, T.E., and Demetris, A.J. (1997). Identification of donor hematopoietic progenitor cells after allogeneic liver transplantation. Transplantation proceedings 29,1211.
Salazar-Mather, T.P., Orange, J.S., and Biron, C.A. (1998). Early murine cytomegalovirus (MCMV) infection induces liver natural killer (NK) cell inflammation and protection through macrophage inflammatory protein lalpha (MIP-lalpha)-dependent pathways. The Journal of experimental medicine 187,1-14.
Samokhvalov, I.M., Samokhvalova, N.I., and Nishikawa, S. (2007). Cell tracing shows the contribution of the yolk sac to adult haematopoiesis. Nature 446,1056-1061.
Samson, S.I., Richard, O., Tavian, M., Ranson, T., Vosshenrich, C.A., Colucci, F., Buer, J., Grosveld, F., Godin, I., and Di Santo, J.P. (2003). GATA-3 promotes maturation, IFN-gamma production, and liver-specific homing of NK cells. Immunity 19,701-711.
Schulz, C., Gomez Perdiguero, E., Chorro, L., Szabo-Rogers, H., Cagnard, N., Kierdorf, K., Prinz, M., Wu, B., Jacobsen, S.E., Pollard, J.W., et al. (2012). A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336,86-90.
Seaman, W.E., Blackman, M.A., Gindhart, T.D., Roubinian, J.R., Loeb, J.M., and Talal, N. (1978). beta-Estradiol reduces natural killer cells in mice. Journal of immunology 121,2193-2198.
Sheth, K., and Bankey, P. (2001). The liver as an immune organ. Current opinion in critical care 7, 99-104.
Shi, F.D., Ljunggren, H.G., La Cava, A., and Van Kaer, L. (2011). Organ-specific features of natural killer cells. Nature reviews. Immunology 11,658-671.
Shi, X., Moroso, V., Metselaar, H.J., and Kwekkeboom, J. (2012). Long-lived intragraft donor leukocytes or relocated donor HSPCs can cause long-term hematopoietic chimerism after liver transplantation. Hepatology.
Sipkins, D.A., Wei, X., Wu, J.W., Runnels, J.M., Cote, D., Means, T.K., Luster, A.D., Scadden, D.T., and Lin, C.P. (2005). In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature 435,969-973.
Slifka, M.K., Pagarigan, R.R., and Whitton, J.L. (2000). NK markers are expressed on a high percentage of virus-specific CD8+ and CD4+ T cells. Journal of immunology 164, 2009-2015.
Small, C.L., McCormick, S., Gill, N., Kugathasan, K., Santosuosso, M., Donaldson, N., Heinrichs, D.E., Ashkar, A., and Xing, Z. (2008). NK cells play a critical protective role in host defense against acute extracellular Staphylococcus aureus bacterial infection in the lung. Journal of immunology 180,5558-5568.
Soderstrom, K., Stein, E., Colmenero, P., Purath, U., Muller-Ladner, U., de Matos, C.T., Tarner, I.H., Robinson, W.H., and Engleman, E.G (2010). Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis. Proceedings of the National Academy of Sciences of the United States of America 107,13028-13033.
Spangrude, G.J., Heimfeld, S., and Weissman, I.L. (1988). Purification and characterization of mouse hematopoietic stem cells. Science 241,58-62.
Sun, J.C., Beilke, J.N., and Lanier, L.L. (2009). Adaptive immune features of natural killer cells. Nature 457,557-561.
Takasaki, S., and Hano, H. (2001). Three-dimensional observations of the human hepatic artery (Arterial system in the liver). Journal of hepatology 34,455-466.
Takeda, K., Cretney, E., Hayakawa, Y., Ota, T., Akiba, H., Ogasawara, K., Yagita, H., Kinoshita, K., Okumura, K., and Smyth, M.J. (2005). TRAIL identifies immature natural killer cells in newborn mice and adult mouse liver. Blood 105,2082-2089.
Taniguchi, H., Toyoshima, T., Fukao, K., and Nakauchi, H. (1996). Presence of hematopoietic stem cells in the adult liver. Nature medicine 2,198-203.
Thompson, A J., and Locarnini, S.A. (2007). Toll-like receptors, RIG-I-like RNA helicases and the antiviral innate immune response. Immunology and cell biology 85,435-445.
Till, J.E., and Me, C.E. (1961). A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiation research 14,213-222.
Townsend, M.J., Weinmann, A.S., Matsuda, J.L., Salomon, R., Farnham, P.J., Biron, C.A., Gapin, L., and Glimcher, L.H. (2004). T-bet regulates the terminal maturation and homeostasis of NK and Valphal4i NKT cells. Immunity 20,477-494.
Uchida, N., Fujisaki, T., Eaves, A.C., and Eaves, C.J. (2001). Transplantable hematopoietic stem cells in human fetal liver have a CD34(+) side population (SP)phenotype. The Journal of clinical investigation 108,1071-1077.
Uchida, N., Leung, F.Y., and Eaves, C.J. (2002). Liver and marrow of adult mdr-la/lb(-/-) mice show normal generation, function, and multi-tissue trafficking of primitive hematopoietic cells. Experimental hematology 30,862-869.
Vivier, E., Raulet, D.H., Moretta, A., Caligiuri, M.A., Zitvogel, L., Lanier, L.L., Yokoyama, W.M., and Ugolini, S. (2011). Innate or adaptive immunity? The example of natural killer cells. Science 331,44-49.
Vivier, E., Tomasello, E., Baratin, M., Walzer, T., and Ugolini, S. (2008). Functions of natural killer cells. Nature immunology 9,503-510.
Vollmar, B., and Menger, M.D. (2009). The hepatic microcirculation:mechanistic contributions and therapeutic targets in liver injury and repair. Physiological reviews 89,1269-1339.
Vonarbourg, C., Mortha, A., Bui, V.L., Hernandez, P.P., Kiss, E.A., Hoyler, T., Flach, M., Bengsch, B., Thimme, R., Holscher, C., et al. (2010). Regulated expression of nuclear receptor RORgammat confers distinct functional fates to NK cell receptor-expressing RORgammat(+) innate lymphocytes. Immunity 33,736-751.
Vosshenrich, C.A., and Di Santo, J.P. (2013). Developmental programming of natural killer and innate lymphoid cells. Current opinion in immunology.
Vosshenrich, C.A., Garcia-Ojeda, M.E., Samson-Villeger, S.I., Pasqualetto, V., Enault, L., Richard-Le Goff, O., Corcuff, E., Guy-Grand, D., Rocha, B., Cumano, A., et al. (2006). A thymic pathway of mouse natural killer cell development characterized by expression of GATA-3 and CD127. Nature immunology 7,1217-1224.
Wagers, A.J., Christensen, J.L., and Weissman, I.L. (2002). Cell fate determination from stem cells. Gene therapy 9,606-612.
Walzer, T., Blery, M., Chaix, J., Fuseri, N., Chasson, L., Robbins, S.H., Jaeger, S., Andre, P., Gauthier, L., Daniel, L., et al. (2007). Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46. Proceedings of the National Academy of Sciences of the United States of America 104,3384-3389.
Walzer, T., Dalod, M., Robbins, S.H., Zitvogel, L., and Vivier, E. (2005). Natural-killer cells and dendritic cells:"1' union fait la force". Blood 106,2252-2258.
Wang, X.Q., Lo, C.M., Chen, L., Cheung, C.K., Yang, Z.F., Chen, Y.X., Ng, M.N., Yu, W.C., Ming, X., Zhang, W., et al. (2012). Hematopoietic chimerism in liver transplantation patients and hematopoietic stem/progenitor cells in adult human liver. Hepatology 56,1557-1566.
Weishaupt, H., Sigvardsson, M., and Attema, J.L. (2010). Epigenetic chromatin states uniquely define the developmental plasticity of murine hematopoietic stem cells. Blood 115,247-256.
Welsh, R.M., Lin, M.Y., Lohman, B.L., Varga, S.M., Zarozinski, C.C., and Selin, L.K. (1997). Alpha beta and gamma delta T-cell networks and their roles in natural resistance to viral infections. Immunological reviews 159,79-93.
Wick, M.J., Leithauser, F., and Reimann, J. (2002). The hepatic immune system. Critical reviews in immunology 22,47-103.
Winau, F., Quack, C., Darmoise, A., and Kaufmann, S.H. (2008). Starring stellate cells in liver immunology. Current opinion in immunology 20,68-74.
Yang, L., Bryder, D., Adolfsson, J., Nygren, J., Mansson, R., Sigvardsson, M., and Jacobsen, S.E. (2005). Identification of Lin(-)Scal(+)kit(+)CD34(+)Flt3-short-term hematopoietic stem cells capable of rapidly reconstituting and rescuing myeloablated transplant recipients. Blood 105,2717-2723.
Yoder, M.C., Hiatt, K., Dutt, P., Mukherjee, P., Bodine, D.M., and Orlic, D. (1997). Characterization of definitive lymphohematopoietic stem cells in the day 9 murine yolk sac. Immunity 7,335-344.
Yokota, Y, Mansouri, A., Mori, S., Sugawara, S., Adachi, S., Nishikawa, S., and Gruss, P. (1999). Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature 397,702-706.
Yoshihara, H., Arai, F., Hosokawa, K., Hagiwara, T., Takubo, K., Nakamura, Y, Gomei, Y, Iwasaki, H., Matsuoka, S., Miyamoto, K., et al. (2007). Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell stem cell 1,685-697.
Zeng, H., Yucel, R., Kosan, C., Klein-Hitpass, L., and Moroy, T. (2004). Transcription factor Gfil regulates self-renewal and engraftment of hematopoietic stem cells. The EMBO journal 23, 4116-4125.
Zhang, J., Niu, C., Ye, L., Huang, H., He, X., Tong, W.G., Ross, J., Haug, J., Johnson, T., Feng, J.Q., et al. (2003). Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425,836-841.