The study of human hematopoiesis is conditioned by access to nondiseased human tissue samples that harbor the cellular substrates for this developmental process. Technical and ethical concerns limit the availability to tissues derived from the fetal and newborn periods, while adult samples are generally restricted to peripheral blood. Access to a small animal model that faithfully recapitulates the process of human hematopoiesis would provide an important tool. Natural killer (NK) cells comprise between 10% and 15% of human peripheral blood lymphocytes and appear conserved in several species. NK cells are implicated in the recognition of pathogen-infected cells and in the clearance of certain tumor cells. In this chapter, we discuss NK cell developmental pathways and the use of humanized murine models for the study of human hematopoiesis and, in particular, human NK cell development.
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References
Anfossi, N., Andre, P., Guia, S., Falk, C. S., Roetynck, S., Stewart, C. A., Breso, V., Frassati, C., Reviron, D., Middleton, D. et al. (2006). Human NK cell education by inhibitory receptors for MHC class I. Immunity25, 331–342.
Baenziger, S., Tussiwand, R., Schlaepfer, E., Mazzucchelli, L., Heikenwalder, M., Kurrer, M. O., Behnke, S., Frey, J., Oxenius, A., Joller, H. et al. (2006). Disseminated and sustained HIV infection in CD34+ cord blood cell-transplanted Rag2−/−γc−/− mice. Proc Natl Acad Sci USA103, 15951–15956.
Barton, K., Muthusamy, N., Fischer, C., Ting, C. N., Walunas, T. L., Lanier, L. L., and Leiden, J. M. (1998). The Ets-1 transcription factor is required for the development of natural killer cells in mice. Immunity9, 555–563.
Bennett, I. M., Zatsepina, O., Zamai, L., Azzoni, L., Mikheeva, T., and Perussia, B. (1996). Definition of a natural killer NKR−P1A+/CD56−/CD16− functionally immature human NK cell subset that differentiates in vitro in the presence of interleukin 12. J Exp Med184, 1845–1856.
Biron, C. A., Nguyen, K. B., Pien, G. C., Cousens, L. P., and Salazar-Mather, T. P. (1999). Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol17, 189–220.
Bix, M., Liao, N. S., Zijlstra, M., Loring, J., Jaenisch, R., and Raulet, D. (1991). Rejection of class I MHC-deficient haemopoietic cells by irradiated MHC-matched mice. Nature349, 329–331.
Blom, B., and Spits, H. (2006). Development of human lymphoid cells. Annu Rev Immunol24, 287–320.
Buckley, R. H. (2004). Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Annu Rev Immunol22, 625–655.
Carson, W. E., Haldar, S., Baiocchi, R. A., Croce, C. M., and Caligiuri, M. A. (1994). The c-kit ligand suppresses apoptosis of human natural killer cells through the upregulation of bcl-2. Proc Natl Acad Sci USA91, 7553–7557.
Cooper, M. A., Fehniger, T. A., and Caligiuri, M. A. (2001). The biology of human natural killer-cell subsets. Trends Immunol22, 633–640.
De Smedt, M., Hoebeke, I., Reynvoet, K., Leclercq, G., and Plum, J. (2005). Different thresholds of Notch signaling bias human precursor cells toward B-, NK-, monocytic/dendritic-, or T-cell lineage in thymus microenvironment. Blood106, 3498–3506.
Diefenbach, A., Jensen, E. R., Jamieson, A. M., and Raulet, D. H. (2001). Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature413, 165–171.
Di Santo, J. P. (2006). Natural killer cell developmental pathways: a question of balance. Annu Rev Immunol24, 257–286.
Di Santo, J. P., and Vosshenrich, C. A. (2006). Bone marrow versus thymic pathways of natural killer cell development. Immunol Rev214, 35–46.
DiSanto, J. P., Muller, W., Guy-Grand, D., Fischer, A., and Rajewsky, K. (1995). Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. Proc Natl Acad Sci USA92, 377–381.
Farag, S. S., and Caligiuri, M. A. (2006). Human natural killer cell development and biology. Blood Rev20, 123–137.
Fernandez, N. C., Treiner, E., Vance, R. E., Jamieson, A. M., Lemieux, S., and Raulet, D. H. (2005). A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors specific for self-MHC molecules. Blood105, 4416–4423.
Freud, A. G., Becknell, B., Roychowdhury, S., Mao, H. C., Ferketich, A. K., Nuovo, G. J., 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. Immunity22, 295–304.
Freud, A. G., and Caligiuri, M. A. (2006). Human natural killer cell development. Immunol Rev214, 56–72.
Furukawa, H., Yabe, T., Watanabe, K., Miyamoto, R., Miki, A., Akaza, T., Tadokoro, K., Tohma, S., Inoue, T., Yamamoto, K., and Juji, T. (1999). Tolerance of NK and LAK activity for HLA class I-deficient targets in a TAP1-deficient patient (bare lymphocyte syndrome type I). Hum Immunol60, 32–40.
Galy, A., Travis, M., Cen, D., and Chen, B. (1995). Human T, B, natural killer, and dendritic cells arise from a common bone marrow progenitor cell subset. Immunity3, 459–473.
Gimeno, R., Weijer, K., Voordouw, A., Uittenbogaart, C. H., Legrand, N., Alves, N. L., Wijnands, E., Blom, B., and Spits, H. (2004). Monitoring the effect of gene silencing by RNA interference in human CD34+ cells injected into newborn RAG2−/− γc−/− mice: functional inactivation of p53 in developing T cells. Blood104, 3886–3893.
Gorantla, S., Sneller, H., Walters, L., Sharp, J. G., Pirruccello, S. J., West, J. T., Wood, C., Dewhurst, S., Gendelman, H. E., and Poluektova, L. (2007). HIV-1 pathobiology studied in humanized Balb/c-Rag2−/−γc−/− mice. J Virol81, 2700–2712.
Haddad, R., Guardiola, P., Izac, B., Thibault, C., Radich, J., Delezoide, A. L., Baillou, C., Lemoine, F. M., Gluckman, J. C., Pflumio, F., and Canque, B. (2004). Molecular characterization of early human T/NK and B-lymphoid progenitor cells in umbilical cord blood. Blood104, 3918–3926.
Hanna, J., Bechtel, P., Zhai, Y., Youssef, F., McLachlan, K., and Mandelboim, O. (2004). Novel insights on human NK cells’ immunological modalities revealed by gene expression profiling. J Immunol173, 6547–6563.
Heemskerk, M. H., Blom, B., Nolan, G., Stegmann, A. P., Bakker, A. Q., Weijer, K., Res, P. C., and Spits, H. (1997). Inhibition of T cell and promotion of natural killer cell development by the dominant negative helix loop helix factor Id3. J Exp Med186, 1597–1602.
Ikawa, T., Fujimoto, S., Kawamoto, H., Katsura, Y., and Yokota, Y. (2001). Commitment to natural killer cells requires the helix-loop-helix inhibitor Id2. Proc Natl Acad Sci USA98, 5164–5169.
Jaleco, A. C., Blom, B., Res, P., Weijer, K., Lanier, L. L., Phillips, J. H., and Spits, H. (1997). Fetal liver contains committed NK progenitors, but is not a site for development of CD34+ cells into T cells. J Immunol159, 694–702.
Karre, K., Ljunggren, H. G., Piontek, G., and Kiessling, R. (1986). Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature319, 675–678.
Kennedy, M. K., Glaccum, M., Brown, S. N., Butz, E. A., Viney, J. L., Embers, M., Matsuki, N., Charrier, K., Sedger, L., Willis, C. R. et al. (2000). Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med191, 771–780.
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. Nat Immunol3, 523–528.
Kim, S., Poursine-Laurent, J., Truscott, S. M., Lybarger, L., Song, Y. J., Yang, L., French, A. R., Sunwoo, J. B., Lemieux, S., Hansen, T. H., and Yokoyama, W. M. (2005). Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature436, 709–713.
Koka, R., Burkett, P. R., Chien, M., Chai, S., Chan, F., Lodolce, J. P., Boone, D. L., and Ma, A. (2003). Interleukin (IL)-15Ra-deficient natural killer cells survive in normal but not IL-15Ra-deficient mice. J Exp Med197, 977–984.
Lanier, L. L., Le, A. M., Civin, C. I., Loken, M. R., and Phillips, J. H. (1986). The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes. J Immunol136, 4480–4486.
Lanier, L. L., Testi, R., Bindl, J., and Phillips, J. H. (1989). Identity of Leu-19 (CD56) leukocyte differentiation antigen and neural cell adhesion molecule. J Exp Med169, 2233–2238.
Le, P. T., Adams, K. L., Zaya, N., Mathews, H. L., Storkus, W. J., and Ellis, T. M. (2001). Human thymic epithelial cells inhibit IL-15- and IL-2-driven differentiation of NK cells from the early human thymic progenitors. J Immunol166, 2194–2201.
Legrand, N., Cupedo, T., van Lent, A. U., Ebeli, M. J., Weijer, K., Hanke, T., and Spits, H. (2006a). Transient accumulation of human mature thymocytes and regulatory T cells with CD28 superagonist in “human immune system” Rag2−/−γc −/− mice. Blood108, 238–245.
Legrand, N., Weijer, K., and Spits, H. (2006b). Experimental models to study development and function of the human immune system in vivo. J Immunol176, 2053–2058.
Lodoen, M. B., and Lanier, L. L. (2005). Viral modulation of NK cell immunity. Nat Rev Microbiol3, 59–69.
Lodolce, J. P., Boone, D. L., Chai, S., Swain, R. E., Dassopoulos, T., Trettin, S., and Ma, A. (1998). IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity9, 669–676.
Lohoff, M., Duncan, G. S., Ferrick, D., Mittrucker, H. W., Bischof, S., Prechtl, S., Rollinghoff, M., Schmitt, E., Pahl, A., and Mak, T. W. (2000). Deficiency in the transcription factor interferon regulatory factor (IRF)-2 leads to severely compromised development of natural killer and T helper type 1 cells. J Exp Med192, 325–336.
Loza, M. J., and Perussia, B. (2004). The IL-12 signature: NK cell terminal CD56+high stage and effector functions. J Immunol172, 88–96.
Macchiarini, F., Manz, M. G., Palucka, A. K., and Shultz, L. D. (2005). Humanized mice: are we there yet? J Exp Med202, 1307–1311.
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-g for TH1 priming. Nat Immunol5, 1260–1265.
McCune, J. M. (1997). Animal models of HIV-1 disease. Science278, 2141–2142.
McCune, J. M., Namikawa, R., Kaneshima, H., Shultz, L. D., Lieberman, M., and Weissman, I. L. (1988). The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science241, 1632–1639.
Miller, J. S., Alley, K. A., and McGlave, P. (1994). 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. Blood83, 2594–2601.
Miller, J. S., and McCullar, V. (2001). Human natural killer cells with polyclonal lectin and immunoglobulinlike receptors develop from single hematopoietic stem cells with preferential expression of NKG2A and KIR2DL2/L3/S2. Blood98, 705–713.
Morandi, B., Bougras, G., Muller, W. A., Ferlazzo, G., and Munz, C. (2006). NK cells of human secondary lymphoid tissues enhance T cell polarization via IFN-g secretion. Eur J Immunol36, 2394–2400.
Mrozek, E., Anderson, P., and Caligiuri, M. A. (1996). Role of interleukin-15 in the development of human CD56+ natural killer cells from CD34+ hematopoietic progenitor cells. Blood87, 2632–2640.
Namikawa, R., Kaneshima, H., Lieberman, M., Weissman, I. L., and McCune, J. M. (1988). Infection of the SCID-hu mouse by HIV-1. Science242, 1684–1686.
Nosaka, T., van Deursen, J. M., Tripp, R. A., Thierfelder, W. E., Witthuhn, B. A., McMickle, A. P., Doherty, P. C., Grosveld, G. C., and Ihle, J. N. (1995). Defective lymphoid development in mice lacking Jak3. Science270, 800–802.
Ogasawara, K., Hida, S., Azimi, N., Tagaya, Y., Sato, T., Yokochi-Fukuda, T., Waldmann, T. A., Taniguchi, T., and Taki, S. (1998). Requirement for IRF-1 in the microenvironment supporting development of natural killer cells. Nature391, 700–703.
Parham, P. (2006). Taking license with natural killer cell maturation and repertoire development. Immunol Rev214, 155–160.
Park, S. Y., Saijo, K., Takahashi, T., Osawa, M., Arase, H., Hirayama, N., Miyake, K., Nakauchi, H., Shirasawa, T., and Saito, T. (1995). Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. Immunity3, 771–782.
Res, P., Martinez-Caceres, E., Cristina Jaleco, A., Staal, F., Noteboom, E., Weijer, K., and Spits, H. (1996). CD34+CD38dim cells in the human thymus can differentiate into T, natural killer, and dendritic cells but are distinct from pluripotent stem cells. Blood87, 5196–5206.
Roder, J. C., Arlund-Richter, L., and Jondal, M. (1979). Target-effector interaction in the human and murine natural killer system: specificity and xenogeneic reactivity of the solubilized natural killer-target structure complex and its loss in a somatic cell hybrid. J Exp Med150, 471–481.
Roifman, C. M., Zhang, J., Chitayat, D., and Sharfe, N. (2000). A partial deficiency of interleukin-7Rα is sufficient to abrogate T-cell development and cause severe combined immunodeficiency. Blood96, 2803–2807.
Rossi, M. I., Yokota, T., Medina, K. L., Garrett, K. P., Comp, P. C., Schipul, A. H., Jr., and Kincade, P. W. (2003). B lymphopoiesis is active throughout human life, but there are developmental age-related changes. Blood101, 576–584.
Ryan, D. H., Nuccie, B. L., Ritterman, I., Liesveld, J. L., Abboud, C. N., and Insel, R. A. (1997). Expression of interleukin-7 receptor by lineage-negative human bone marrow progenitors with enhanced lymphoid proliferative potential and B-lineage differentiation capacity. Blood89, 929–940.
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-γ production, and liver-specific homing of NK cells. Immunity19, 701–711.
Sarun, S., Dalloul, A. H., Laurent, C., Blanc, C., and Schmitt, C. (1998). Human CD34+ thymocyte maturation: pre-T and NK cell differentiation on neonatal thymic stromal cell culture. Cell Immunol190, 23–32.
Sato, T., Laver, J. H., Aiba, Y., and Ogawa, M. (1999). NK cell colony formation from human fetal thymocytes. Exp Hematol27, 726–733.
Schotte, R., Nagasawa, M., Weijer, K., Spits, H., and Blom, B. (2004). The ETS transcription factor Spi-B is required for human plasmacytoid dendritic cell development. J Exp Med200, 1503–1509.
Schotte, R., Rissoan, M. C., Bendriss-Vermare, N., Bridon, J. M., Duhen, T., Weijer, K., Briere, F., and Spits, H. (2003). The transcription factor Spi-B is expressed in plasmacytoid DC precursors and inhibits T-, B-, and NK-cell development. Blood101, 1015–1023.
Spits, H., Blom, B., Jaleco, A. C., Weijer, K., Verschuren, M. C., van Dongen, J. J., Heemskerk, M. H., and Res, P. C. (1998). Early stages in the development of human T, natural killer and thymic dendritic cells. Immunol Rev165, 75–86.
Spits, H., Lanier, L. L., and Phillips, J. H. (1995). Development of human T and natural killer cells. Blood85, 2654–2670.
Suzuki, H., Duncan, G. S., Takimoto, H., and Mak, T. W. (1997). Abnormal development of intestinal intraepithelial lymphocytes and peripheral natural killer cells in mice lacking the IL-2 receptor beta chain. J Exp Med185, 499–505.
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 Valpha14i NKT cells. Immunity20, 477–494.
Traggiai, E., Chicha, L., Mazzucchelli, L., Bronz, L., Piffaretti, J. C., Lanzavecchia, A., and Manz, M. G. (2004). Development of a human adaptive immune system in cord blood cell-transplanted mice. Science304, 104–107.
Trinchieri, G. (1989). Biology of natural killer cells. Adv Immunol47, 187–376.
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. Nat Immunol7, 1217–1224.
Yokoyama, W. M., and Kim, S. (2006). Licensing of natural killer cells by self-major histocompatibility complex class I. Immunol Rev214, 143–154.
Yokoyama, W. M., Kim, S., and French, A. R. (2004). The dynamic life of natural killer cells. Annu Rev Immunol22, 405–429.
Zhang, L., Kovalev, G. I., and Su, L. (2007). HIV-1 infection and pathogenesis in a novel humanized mouse model. Blood109, 2978–2981.
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Huntington, N.D., Di Santo, J.P. (2008). Humanized Immune System (HIS) Mice as a Tool to Study Human NK Cell Development. In: Nomura, T., Watanabe, T., Habu, S. (eds) Humanized Mice. Current Topics in Microbiology and Immunology, vol 324. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-75647-7_7
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