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The Role of NK Cells and Their Exosomes in Graft Versus Host Disease and Graft Versus Leukemia

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Abstract

Natural killer (NK) cells are one of the innate immune cells that play an important role in preventing and controlling tumors and viral diseases, but their role in hematopoietic stem cell transplantation (HCT) is not yet fully understood. However, according to some research, these cells can prevent infections and tumor relapse without causing graft versus host disease (GVHD). In addition to NK cells, several studies are about the anti-leukemia effects of NK cell-derived exosomes that can highlight their roles in graft-versus-leukemia (GVL). In this paper, we intend to investigate the results of various articles on the role of NK cells in allogeneic hematopoietic cell transplantation and also their exosomes in GVL. Also, we have discussed the antiviral effects of these cells in post-HCT cytomegalovirus infection.

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References

  1. Herberman, R. B., Nunn, M. E., & Lavrin, D. H. (1975). Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. I. Distribution of reactivity and specificity. International Journal of Cancer, 16(2), 216–229.

    Article  CAS  Google Scholar 

  2. Kiessling, R., Klein, E., & 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(2), 112–117.

    Article  CAS  Google Scholar 

  3. Miller, J. S., McCullar, V., Punzel, M., Lemischka, I. R., & Moore, K. A. (1999). Single adult human CD34+/Lin–/CD38 – progenitors give rise to natural killer cells, B-lineage cells, dendritic cells, and myeloid cells. Blood the Journal of the American Society of Hematology, 93(1), 96–106.

    CAS  Google Scholar 

  4. Luetke-Eversloh, M., Killig, M., & Romagnani, C. (2013). Signatures of human NK cell development and terminal differentiation. Frontiers in Immunology, 4, 499.

    Article  Google Scholar 

  5. Vacca, P., Montaldo, E., Croxatto, D., Moretta, F., Bertaina, A., Vitale, C., et al. (2016). NK cells and other innate lymphoid cells in hematopoietic stem cell transplantation. Frontiers in Immunology, 7, 188.

    Article  Google Scholar 

  6. Abrahamsen, I. W., Somme, S., Heldal, D., Egeland, T., Kvale, D., & Tjonnfjord, G. (2005). Immune reconstitution after allogeneic stem cell transplantation: the impact of stem cell source and graft-versus-host disease. Haematologica, 90(1), 86–93.

    Google Scholar 

  7. de Koning, C., Plantinga, M., Besseling, P., Boelens, J. J., & Nierkens, S. (2016). Immune reconstitution after allogeneic hematopoietic cell transplantation in children. Biology of Blood and Marrow Transplantation, 22(2), 195–206.

    Article  Google Scholar 

  8. Lupo, K. B., & Matosevic, S. (2019). Natural killer cells as allogeneic effectors in adoptive cancer immunotherapy. Cancers, 11(6), 769.

    Article  CAS  Google Scholar 

  9. Vitale, M., Cantoni, C., Della Chiesa, M., Ferlazzo, G., Carlomagno, S., Pende, D., et al. (2019). An historical overview: the discovery of how NK cells can kill enemies, recruit defense troops, and more. Frontiers in Immunology, 10, 1415.

    Article  CAS  Google Scholar 

  10. Yu, Y., Kumar, V., & Bennett, M. (1992). Murine natural killer cells and marrow graft rejection. Annual Review of Immunology, 10(1), 189–213.

    Article  CAS  Google Scholar 

  11. Taghavi-Farahabadi, M., Mahmoudi, M., Mahdaviani, S. A., Baghaei, K., Rayzan, E., Hashemi, S. M., et al. (2020). Improving the function of neutrophils from chronic granulomatous disease patients using mesenchymal stem cells’ exosomes. Human Immunology, 81(10–11), 614–624.

    Article  CAS  Google Scholar 

  12. Hazrati, A., Soudi, S., Malekpour, K., Mahmoudi, M., Rahimi, A., Hashemi, S. M., et al. (2022). Immune cells-derived exosomes function as a double-edged sword: role in disease progression and their therapeutic applications. Biomarker Research, 10(1), 1–25.

    Article  Google Scholar 

  13. Gill, S., Olson, J. A., & Negrin, R. S. (2009). Natural killer cells in allogeneic transplantation: effect on engraftment, graft-versus-tumor, and graft-versus-host responses. Biology of Blood and Marrow Transplantation, 15(7), 765–776.

    Article  CAS  Google Scholar 

  14. Locatelli, F., Pende, D., Maccario, R., Mingari, M. C., Moretta, A., & Moretta, L. (2009). Haploidentical hemopoietic stem cell transplantation for the treatment of high-risk leukemias: how NK cells make the difference. Clinical Immunology, 133(2), 171–178.

    Article  CAS  Google Scholar 

  15. Abel, A. M., Yang, C., Thakar, M. S., & Malarkannan, S. (2018). Natural killer cells: development, maturation, and clinical utilization. Frontiers in Immunology, 9, 1869.

    Article  Google Scholar 

  16. Cooper, M. A., Fehniger, T. A., & Caligiuri, M. A. (2001). The biology of human natural killer-cell subsets. Trends in Immunology, 22(11), 633–640.

    Article  CAS  Google Scholar 

  17. Ullah, M. A., Hill, G. R., & Tey, S. K. (2016). Functional reconstitution of natural killer cells in allogeneic hematopoietic stem cell transplantation. Frontiers in Immunology, 7, 144.

    Article  Google Scholar 

  18. Fauriat, C., Long, E. O., Ljunggren, H. G., & Bryceson, Y. T. (2010). Regulation of human NK-cell cytokine and chemokine production by target cell recognition. Blood, 115(11), 2167–2176.

    Article  CAS  Google Scholar 

  19. Fehniger, T. A., Cooper, M. A., Nuovo, G. J., Cella, M., Facchetti, F., Colonna, M., et al. (2003). CD56bright natural killer cells are present in human lymph nodes and are activated by T cell–derived IL-2: a potential new link between adaptive and innate immunity. Blood the Journal of the American Society of Hematology, 101(8), 3052–3057.

    CAS  Google Scholar 

  20. Ferlazzo, G., Thomas, D., Lin, S. L., Goodman, K., Morandi, B., Muller, W. A., et al. (2004). The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic. The Journal of Immunology, 172(3), 1455–1462.

    Article  CAS  Google Scholar 

  21. Dogra, P., Rancan, C., Ma, W., Toth, M., Senda, T., Carpenter, D. J., et al. (2020). Tissue determinants of human NK cell development, function, and residence. Cell, 180(4), 749–763. e13.

    Article  CAS  Google Scholar 

  22. Ali, T. H., Pisanti, S., Ciaglia, E., Mortarini, R., Anichini, A., Garofalo, C., et al. (2014). Enrichment of CD56 dim KIR + CD57 + highly cytotoxic NK cells in tumour-infiltrated lymph nodes of melanoma patients. Nature Communications, 5(1), 1–9.

    Article  CAS  Google Scholar 

  23. Jacobs, R., Hintzen, G., Kemper, A., Beul, K., Kempf, S., Behrens, G., et al. (2001). CD56bright cells differ in their KIR repertoire and cytotoxic features from CD56dim NK cells. European Journal of Immunology, 31(10), 3121–3126.

    Article  CAS  Google Scholar 

  24. Björkström, N. K., Riese, P., Heuts, F., Andersson, S., Fauriat, C., Ivarsson, M. A., et al. (2010). Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education. Blood, 116(19), 3853–3864.

    Article  Google Scholar 

  25. Wu, F., Xie, M., Hun, M., She, Z., Li, C., Luo, S., et al. (2021). Natural killer cell-derived extracellular vesicles: novel players in cancer immunotherapy. Frontiers in Immunology, 12, 1970.

    Google Scholar 

  26. Wu, C. H., Li, J., Li, L., Sun, J., Fabbri, M., Wayne, A. S., et al. (2019). Extracellular vesicles derived from natural killer cells use multiple cytotoxic proteins and killing mechanisms to target cancer cells. Journal of Extracellular Vesicles, 8(1), 1588538.

    Article  CAS  Google Scholar 

  27. Neviani, P., Wise, P. M., Murtadha, M., Liu, C. W., Wu, C. H., Jong, A. Y., et al. (2019). Natural killer–derived exosomal miR-186 inhibits neuroblastoma growth and immune escape mechanisms. Cancer Research, 79(6), 1151–1164.

    Article  CAS  Google Scholar 

  28. Lugini, L., Cecchetti, S., Huber, V., Luciani, F., Macchia, G., Spadaro, F., et al. (2012). Immune surveillance properties of human NK cell-derived exosomes. The Journal of Immunology, 189(6), 2833–2842.

    Article  CAS  Google Scholar 

  29. Zhu, L., Kalimuthu, S., Oh, J. M., Gangadaran, P., Baek, S. H., Jeong, S. Y., et al. (2019). Enhancement of antitumor potency of extracellular vesicles derived from natural killer cells by IL-15 priming. Biomaterials, 190, 38–50.

    Article  Google Scholar 

  30. Shilling, H. G., McQueen, K. L., Cheng, N. W., Shizuru, J. A., Negrin, R. S., & Parham, P. (2003). Reconstitution of NK cell receptor repertoire following HLA-matched hematopoietic cell transplantation. Blood the Journal of the American Society of Hematology, 101(9), 3730–3740.

    CAS  Google Scholar 

  31. Chang, Y. J., Zhao, X. Y., & Huang, X. J. (2008). Effects of the NK cell recovery on outcomes of unmanipulated haploidentical blood and marrow transplantation for patients with hematologic malignancies. Biology of Blood and Marrow Transplantation, 14(3), 323–334.

    Article  Google Scholar 

  32. Suen, W. C. W., Lee, W. Y. W., Leung, K. T., Pan, X. H., & Li, G. (2018). Natural killer cell-based cancer immunotherapy: a review on 10 years completed clinical trials. Cancer Investigation, 36(8), 431–457.

    Article  CAS  Google Scholar 

  33. Velardi, A., Ruggeri, L., Mancusi, A., Aversa, F., & Christiansen, F. T. (2009). Natural killer cell allorecognition of missing self in allogeneic hematopoietic transplantation: a tool for immunotherapy of leukemia. Current Opinion in Immunology, 21(5), 525–530.

    Article  CAS  Google Scholar 

  34. Parham, P. (2005). MHC class I molecules and KIRs in human history, health and survival. Nature Reviews Immunology, 5(3), 201–214.

    Article  CAS  Google Scholar 

  35. Pyo, C. W., Wang, R., Vu, Q., Cereb, N., Yang, S. Y., Duh, F. M., et al. (2013). Recombinant structures expand and contract inter and intragenic diversification at the KIR locus. BMC Genomics, 14(1), 89.

    Article  CAS  Google Scholar 

  36. Shilling, H. G., Young, N., Guethlein, L. A., Cheng, N. W., Gardiner, C. M., Tyan, D., et al. (2002). Genetic control of human NK cell repertoire. The Journal of Immunology, 169(1), 239–247.

    Article  CAS  Google Scholar 

  37. Uhrberg, M., Valiante, N. M., Shum, B. P., Shilling, H. G., Lienert-Weidenbach, K., Corliss, B., et al. (1997). Human diversity in killer cell inhibitory receptor genes. Immunity, 7(6), 753–763.

    Article  CAS  Google Scholar 

  38. Winter, C. C., Gumperz, J. E., Parham, P., Long, E. O., & Wagtmann, N. (1998). Direct binding and functional transfer of NK cell inhibitory receptors reveal novel patterns of HLA-C allotype recognition. The Journal of Immunology, 161(2), 571–577.

    Article  CAS  Google Scholar 

  39. Moesta, A. K., & Parham, P. (2012). Diverse functionality among human NK cell receptors for the C1 epitope of HLA-C: KIR2DS2, KIR2DL2, and KIR2DL3. Frontiers in Immunology, 3, 336.

    Article  Google Scholar 

  40. Rajagopalan, S., & Long, E. O. (2012). KIR2DL4 (CD158d): an activation receptor for HLA-G. Frontiers in Immunology, 3, 258.

    Article  Google Scholar 

  41. Carr, W. H., Pando, M. J., & Parham, P. (2005). KIR3DL1 polymorphisms that affect NK cell inhibition by HLA-Bw4 ligand. The Journal of Immunology, 175(8), 5222–5229.

    Article  CAS  Google Scholar 

  42. Goodridge, J. P., Burian, A., Lee, N., & Geraghty, D. E. (2013). HLA-F and MHC class I open conformers are ligands for NK cell Ig-like receptors. The Journal of Immunology, 191(7), 3553–3562.

    Article  CAS  Google Scholar 

  43. Hansasuta, P., Dong, T., Thananchai, H., Weekes, M., Willberg, C., Aldemir, H., et al. (2004). Recognition of HLA-A3 and HLA‐A11 by KIR3DL2 is peptide‐specific. European Journal of Immunology, 34(6), 1673–1679.

    Article  CAS  Google Scholar 

  44. Thielens, A., Vivier, E., & Romagné, F. (2012). NK cell MHC class I specific receptors (KIR): from biology to clinical intervention. Current Opinion in Immunology, 24(2), 239–245.

    Article  CAS  Google Scholar 

  45. Moretta, A., Bottino, C., Pende, D., Tripodi, G., Tambussi, G., Viale, O., et al. (1990). Identification of four subsets of human CD3-CD16 + natural killer (NK) cells by the expression of clonally distributed functional surface molecules: correlation between subset assignment of NK clones and ability to mediate specific alloantigen recognition. The Journal of Experimental Medicine, 172(6), 1589–1598.

    Article  CAS  Google Scholar 

  46. Ljunggren, H. G., & Kärre, K. (1990). In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunology Today, 11, 237–244.

    Article  CAS  Google Scholar 

  47. Davies, S. M., Ruggieri, L., DeFor, T., Wagner, J. E., Weisdorf, D. J., Miller, J. S., et al. (2002). Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Blood, 100(10), 3825–3827.

    Article  CAS  Google Scholar 

  48. Symons, H. J., Leffell, M. S., Rossiter, N. D., Zahurak, M., Jones, R. J., & Fuchs, E. J. (2010). Improved survival with inhibitory killer immunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors after nonmyeloablative, HLA-haploidentical bone marrow transplantation. Biology of Blood and Marrow Transplantation, 16(4), 533–542.

    Article  Google Scholar 

  49. Pende, D., Marcenaro, S., Falco, M., Martini, S., Bernardo, M. E., Montagna, D., et al. (2009). Anti-leukemia activity of alloreactive NK cells in KIR ligand-mismatched haploidentical HSCT for pediatric patients: evaluation of the functional role of activating KIR and redefinition of inhibitory KIR specificity. Blood the Journal of the American Society of Hematology, 113(13), 3119–3129.

    CAS  Google Scholar 

  50. Clausen, J., Wolf, D., Petzer, A., Gunsilius, E., Schumacher, P., Kircher, B., et al. (2007). Impact of natural killer cell dose and donor killer-cell immunoglobulin‐like receptor (KIR) genotype on outcome following human leucocyte antigen‐identical haematopoietic stem cell transplantation. Clinical & Experimental Immunology, 148(3), 520–528.

    Article  CAS  Google Scholar 

  51. Wang, W., Erbe, A. K., DeSantes, K. B., & Sondel, P. M. (2017). Donor selection for ex vivo-expanded natural killer cells as adoptive cancer immunotherapy. Future Oncology, 13(12), 1043–1047. https://doi.org/10.2217/fon-2017-0039

    Article  CAS  Google Scholar 

  52. Sivori, S., Falco, M., Carlomagno, S., Romeo, E., Soldani, C., Bensussan, A., et al. (2010). A novel KIR-associated function: evidence that CpG DNA uptake and shuttling to early endosomes is mediated by KIR3DL2. Blood, 116(10), 1637–1647.

    Article  CAS  Google Scholar 

  53. Jiang, W., Johnson, C., Jayaraman, J., Simecek, N., Noble, J., Moffatt, M. F., et al. (2012). Copy number variation leads to considerable diversity for B but not A haplotypes of the human KIR genes encoding NK cell receptors. Genome Research, 22(10), 1845–1854.

    Article  CAS  Google Scholar 

  54. Martin, A. M., Kulski, J. K., Gaudieri, S., Witt, C. S., Freitas, E. M., Trowsdale, J., et al. (2004). Comparative genomic analysis, diversity and evolution of two KIR haplotypes A and B. Gene, 335, 121–131.

    Article  CAS  Google Scholar 

  55. Bachanova, V., Weisdorf, D. J., Wang, T., Marsh, S. G., Trachtenberg, E., Haagenson, M. D., et al. (2016). Donor KIR B genotype improves progression-free survival of non-Hodgkin lymphoma patients receiving unrelated donor transplantation. Biology of Blood and Marrow Transplantation, 22(9), 1602–1607.

    Article  Google Scholar 

  56. Impola, U., Turpeinen, H., Alakulppi, N., Linjama, T., Volin, L., Niittyvuopio, R., et al. (2014). Donor haplotype B of NK KIR receptor reduces the relapse risk in HLA-identical sibling hematopoietic stem cell transplantation of AML patients. Frontiers in Immunology, 5, 405.

    Article  Google Scholar 

  57. Oevermann, L., Michaelis, S. U., Mezger, M., Lang, P., Toporski, J., Bertaina, A., et al. (2014). KIR B haplotype donors confer a reduced risk for relapse after haploidentical transplantation in children with ALL. Blood the Journal of the American Society of Hematology, 124(17), 2744–2747.

    CAS  Google Scholar 

  58. Cooley, S., Weisdorf, D. J., Guethlein, L. A., Klein, J. P., Wang, T., Le, C. T., et al. (2010). Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood, 116(14), 2411–2419.

    Article  CAS  Google Scholar 

  59. Pyo, C. W., Guethlein, L. A., Vu, Q., Wang, R., Abi-Rached, L., Norman, P. J., et al. (2010). Different patterns of evolution in the centromeric and telomeric regions of group A and B haplotypes of the human killer cell Ig-like receptor locus. PLoS One, 5(12), e15115.

    Article  CAS  Google Scholar 

  60. Ryan, J. C., & Seaman, W. E. (1997). Divergent functions of lectin-like receptors on NK cells. Immunological Reviews, 155(1), 79–89.

    Article  CAS  Google Scholar 

  61. Braud, V. M., Allan, D. S., O’Callaghan, C. A., Söderström, K., D’Andrea, A., Ogg, G. S., et al. (1998). HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature, 391(6669), 795–799.

    Article  CAS  Google Scholar 

  62. Lee, N., Llano, M., Carretero, M., Ishitani, A., Navarro, F., López-Botet, M., et al. (1998). HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proceedings of the National Academy of Sciences, 95(9), 5199–204.

    Article  CAS  Google Scholar 

  63. Freud, A. G., Yokohama, A., Becknell, B., Lee, M. T., Mao, H. C., Ferketich, A. K., et al. (2006). Evidence for discrete stages of human natural killer cell differentiation in vivo. The Journal of Experimental Medicine, 203(4), 1033–1043.

    Article  CAS  Google Scholar 

  64. Nguyen, S., Dhedin, N., Vernant, J. P., Kuentz, M., Jijakli, A. A., Rouas-Freiss, N., et al. (2005). NK-cell reconstitution after haploidentical hematopoietic stem-cell transplantations: immaturity of NK cells and inhibitory effect of NKG2A override GvL effect. Blood, 105(10), 4135–4142.

    Article  CAS  Google Scholar 

  65. Ruggeri, L., Urbani, E., André, P., Mancusi, A., Tosti, A., Topini, F., et al. (2016). Effects of anti-NKG2A antibody administration on leukemia and normal hematopoietic cells. Haematologica, 101(5), 626–633.

    Article  CAS  Google Scholar 

  66. López-Botet, M., Muntasell, A., & Vilches, C. (Eds.). (2014). The CD94/NKG2C + NK-cell subset on the edge of innate and adaptive immunity to human cytomegalovirus infection. Seminars in Immunology. Elsevier.

  67. Bauer, S., Groh, V., Wu, J., Steinle, A., Phillips, J. H., Lanier, L. L., et al. (1999). Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science, 285(5428), 727–729.

    Article  CAS  Google Scholar 

  68. Billadeau, D. D., Upshaw, J. L., Schoon, R. A., Dick, C. J., & Leibson, P. J. (2003). NKG2D-DAP10 triggers human NK cell–mediated killing via a Syk-independent regulatory pathway. Nature Immunology, 4(6), 557–564.

    Article  CAS  Google Scholar 

  69. Garrity, D., Call, M. E., Feng, J., & Wucherpfennig, K. W. (2005). The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure. Proceedings of the National Academy of Sciences, 102(21), 7641–6.

    Article  CAS  Google Scholar 

  70. Bottino, C., Biassoni, R., Millo, R., Moretta, L., & Moretta, A. (2000). The human natural cytotoxicity receptors (NCR) that induce HLA class I-independent NK cell triggering. Human Immunology, 61(1), 1–6.

    Article  CAS  Google Scholar 

  71. Bottino, C., Moretta, L., & Moretta, A. (2006). NK cell activating receptors and tumor recognition in humans. Immunobiology of Natural Killer Cell Receptors (p. 175–82). Springer. 

  72. Cantoni, C., Bottino, C., Vitale, M., Pessino, A., Augugliaro, R., Malaspina, A., et al. (1999). NKp44, a triggering receptor involved in tumor cell lysis by activated human natural killer cells, is a novel member of the immunoglobulin superfamily. The Journal of Experimental Medicine, 189(5), 787–796.

    Article  CAS  Google Scholar 

  73. Pende, D., Parolini, S., Pessino, A., Sivori, S., Augugliaro, R., Morelli, L., et al. (1999). Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. The Journal of Experimental Medicine, 190(10), 1505–1516.

    Article  CAS  Google Scholar 

  74. Sivori, S., Pende, D., Bottino, C., Marcenaro, E., Pessino, A., Biassoni, R., et al. (1999). NKp46 is the major triggering receptor involved in the natural cytotoxicity of fresh or cultured human NK cells. Correlation between surface density of NKp46 and natural cytotoxicity against autologous, allogeneic or xenogeneic target cells. European Journal of Immunology, 29(5), 1656–1666.

    Article  CAS  Google Scholar 

  75. Barrow, A. D., Edeling, M. A., Trifonov, V., Luo, J., Goyal, P., Bohl, B., et al. (2018). Natural killer cells control tumor growth by sensing a growth factor. Cell, 172(3), 534–548. e19.

    Article  CAS  Google Scholar 

  76. Baychelier, F., Sennepin, A., Ermonval, M., Dorgham, K., Debré, P., & Vieillard, V. (2013). Identification of a cellular ligand for the natural cytotoxicity receptor NKp44. Blood. The Journal of the American Society of Hematology, 122(17), 2935–2942.

    CAS  Google Scholar 

  77. Brandt, C. S., Baratin, M., Yi, E. C., Kennedy, J., Gao, Z., Fox, B., et al. (2009). The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans. Journal of Experimental Medicine, 206(7), 1495–1503.

    Article  CAS  Google Scholar 

  78. Rosental, B., Brusilovsky, M., Hadad, U., Oz, D., Appel, M. Y., Afergan, F., et al. (2011). Proliferating cell nuclear antigen is a novel inhibitory ligand for the natural cytotoxicity receptor NKp44. The Journal of Immunology, 187(11), 5693–5702.

    Article  CAS  Google Scholar 

  79. von Strandmann, E. P., Simhadri, V. R., von Tresckow, B., Sasse, S., Reiners, K. S., Hansen, H. P., et al. (2007). Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells. Immunity, 27(6), 965–974.

    Article  Google Scholar 

  80. Narni-Mancinelli, E., Gauthier, L., Baratin, M., Guia, S., Fenis, A., Deghmane, A. E., Rossi, B., Fourquet, P., Escalière, B., Kerdiles, Y. M., Ugolini, S., Taha, M. K., & Vivier, E. (2017). Complement factor P is a ligand for the natural killer cell-activating receptor NKp46. Science Immunology, 2(10), eaam9628. https://doi.org/10.1126/sciimmunol.aam9628

    Article  Google Scholar 

  81. Del Zotto, G., Marcenaro, E., Vacca, P., Sivori, S., Pende, D., Della Chiesa, M., et al. (2017). Markers and function of human NK cells in normal and pathological conditions. Cytometry Part B: Clinical Cytometry, 92(2), 100–114.

    Article  Google Scholar 

  82. Fauriat, C., Just-Landi, S., Mallet, F., Arnoulet, C., Sainty, D., Olive, D., et al. (2007). Deficient expression of NCR in NK cells from acute myeloid leukemia: Evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction. Blood, 109(1), 323–330.

    Article  CAS  Google Scholar 

  83. Triplett, B. M., Horwitz, E. M., Iyengar, R., Turner, V., Holladay, M. S., Gan, K., et al. (2009). Effects of activating NK cell receptor expression and NK cell reconstitution on the outcomes of unrelated donor hematopoietic cell transplantation for hematologic malignancies. Leukemia, 23(7), 1278–1287.

    Article  CAS  Google Scholar 

  84. Di Pace, A. L., Tumino, N., Besi, F., Alicata, C., Conti, L. A., Munari, E., et al. (2020). Characterization of human NK cell-derived exosomes: Role of DNAM1 receptor in exosome-mediated cytotoxicity against tumor. Cancers, 12(3), 661.

    Article  Google Scholar 

  85. Bottino, C., Castriconi, R., Pende, D., Rivera, P., Nanni, M., Carnemolla, B., et al. (2003). Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. The Journal of Experimental Medicine, 198(4), 557–567.

    Article  CAS  Google Scholar 

  86. Martinet, L., & Smyth, M. J. (2015). Balancing natural killer cell activation through paired receptors. Nature Reviews Immunology, 15(4), 243–254.

    Article  CAS  Google Scholar 

  87. Zhang, Q., Bi, J., Zheng, X., Chen, Y., Wang, H., Wu, W., et al. (2018). Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nature Immunology, 19(7), 723–732.

    Article  CAS  Google Scholar 

  88. Bowles, J. A., Wang, S. Y., Link, B. K., Allan, B., Beuerlein, G., Campbell, M. A., et al. (2006). Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab. Blood, 108(8), 2648–2654.

    Article  CAS  Google Scholar 

  89. Vivier, E., Raulet, D. H., Moretta, A., Caligiuri, M. A., Zitvogel, L., Lanier, L. L., et al. (2011). Innate or adaptive immunity? The example of natural killer cells. Science, 331(6013), 44–49.

    Article  CAS  Google Scholar 

  90. Colonna, M., Navarro, F., Bellón, T., Llano, M., García, P., Samaridis, J., et al. (1997). A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells. The Journal of Experimental Medicine, 186(11), 1809–1818.

    Article  CAS  Google Scholar 

  91. Bessoles, S., Grandclément, C., Alari-Pahissa, E., Gehrig, J., Jeevan-Raj, B., & Held, W. (2014). Adaptations of natural killer cells to self-MHC class I. Frontiers in Immunology, 5, 349.

    Article  Google Scholar 

  92. Stern, M., Passweg, J., Meyer-Monard, S., Esser, R., Tonn, T., Soerensen, J., et al. (2013). Pre-emptive immunotherapy with purified natural killer cells after haploidentical SCT: a prospective phase II study in two centers. Bone Marrow Transplantation, 48(3), 433–438.

    Article  CAS  Google Scholar 

  93. Juelke, K., Killig, M., Thiel, A., Dong, J., & Romagnani, C. (2009). Education of hyporesponsive NK cells by cytokines. European Journal of Immunology, 39(9), 2548–2555.

    Article  CAS  Google Scholar 

  94. Shoae-Hassani, A., Hamidieh, A. A., Behfar, M., Mohseni, R., Mortazavi-Tabatabaei, S. A., & Asgharzadeh, S. (2017). NK cell-derived exosomes from NK cells previously exposed to neuroblastoma cells augment the antitumor activity of cytokine-activated NK cells. Journal of Immunotherapy, 40(7), 265–276. https://doi.org/10.1097/CJI.0000000000000179

    Article  CAS  Google Scholar 

  95. Jong, A. Y., Wu, C. H., Li, J., Sun, J., Fabbri, M., Wayne, A. S., et al. (2017). Large-scale isolation and cytotoxicity of extracellular vesicles derived from activated human natural killer cells. Journal of Extracellular Vesicles, 6(1), 1294368.

    Article  Google Scholar 

  96. Choi, J. W., Lim, S., Kang, J. H., Hwang, S. H., Hwang, K. C., Kim, S. W., et al. (2020). Proteome analysis of human natural killer cell derived extracellular vesicles for identification of anticancer effectors. Molecules, 25(21), 5216.

    Article  CAS  Google Scholar 

  97. Elliott, J. M., & Yokoyama, W. M. (2011). Unifying concepts of MHC-dependent natural killer cell education. Trends in Immunology, 32(8), 364–372.

    Article  CAS  Google Scholar 

  98. Raulet, D. H., & Vance, R. E. (2006). Self-tolerance of natural killer cells. Nature Reviews Immunology, 6(7), 520–531.

    Article  CAS  Google Scholar 

  99. Shifrin, N., Raulet, D. H., & Ardolino, M. (Eds.). (2014). NK cell self tolerance, responsiveness and missing self recognition. Seminars in immunology. Elsevier.

  100. Raulet, D. H. (Ed.). (2006). editor Missing self recognition and self tolerance of natural killer (NK) cells. Seminars in Immunology. Elsevier.

  101. Jonsson, A. H., & Yokoyama, W. M. (2009). Natural killer cell tolerance: licensing and other mechanisms. Advances in Immunology, 101, 27–79.

    Article  CAS  Google Scholar 

  102. Joncker, N. T., Fernandez, N. C., Treiner, E., Vivier, E., & Raulet, D. H. (2009). NK cell responsiveness is tuned commensurate with the number of inhibitory receptors for self-MHC class I: the rheostat model. The Journal of Immunology, 182(8), 4572–4580.

    Article  CAS  Google Scholar 

  103. Foley, B., Cooley, S., Verneris, M. R., Curtsinger, J., Luo, X., Waller, E. K., et al. (2011). NK cell education after allogeneic transplantation: dissociation between recovery of cytokine-producing and cytotoxic functions. Blood the Journal of the American Society of Hematology, 118(10), 2784–2792.

    CAS  Google Scholar 

  104. Yu, J., Venstrom, J. M., Liu, X. R., Pring, J., Hasan, R. S., O’Reilly, R. J., et al. (2009). Breaking tolerance to self, circulating natural killer cells expressing inhibitory KIR for non-self HLA exhibit effector function after T cell–depleted allogeneic hematopoietic cell transplantation. Blood, 113(16), 3875–3884.

    Article  CAS  Google Scholar 

  105. Orr, M. T., Murphy, W. J., & Lanier, L. L. (2010). ’Unlicensed’natural killer cells dominate the response to cytomegalovirus infection. Nature Immunology, 11(4), 321–327.

    Article  CAS  Google Scholar 

  106. Zamora, A. E., Aguilar, E. G., Sungur, C. M., Khuat, L. T., Dunai, C., Lochhead, G. R., Du, J., Pomeroy, C., Blazar, B. R., Longo, D. L., Venstrom, J. M., Baumgarth, N., & Murphy, W. J. (2017). Licensing delineates helper and effector NK cell subsets during viral infection. JCI Insight, 2(10), e87032. https://doi.org/10.1172/jci.insight.87032

    Article  Google Scholar 

  107. Yokoyama, W. M., & Kim, S. (2006). Licensing of natural killer cells by self-major histocompatibility complex class I. Immunological Reviews, 214(1), 143–154.

    Article  CAS  Google Scholar 

  108. Björklund, A. T., Schaffer, M., Fauriat, C., Ringdén, O., Remberger, M., Hammarstedt, C., et al. (2010). NK cells expressing inhibitory KIR for non–self-ligands remain tolerant in HLA-matched sibling stem cell transplantation. Blood the Journal of the American Society of Hematology, 115(13), 2686–2694.

    Google Scholar 

  109. He, Y., & Tian, Z. (2017). NK cell education via nonclassical MHC and non-MHC ligands. Cellular & Molecular Immunology, 14(4), 321–330.

    Article  CAS  Google Scholar 

  110. Tripathy, S. K., Keyel, P. A., Yang, L., Pingel, J. T., Cheng, T. P., Schneeberger, A., et al. (2008). Continuous engagement of a self-specific activation receptor induces NK cell tolerance. The Journal of Experimental Medicine, 205(8), 1829–1841.

    Article  CAS  Google Scholar 

  111. Chewning, J. H., Gudme, C. N., Hsu, K. C., Selvakumar, A., & Dupont, B. (2007). KIR2DS1-positive NK cells mediate alloresponse against the C2 HLA-KIR ligand group in vitro. The Journal of Immunology, 179(2), 854–868.

    Article  CAS  Google Scholar 

  112. Venstrom, J. M., Pittari, G., Gooley, T. A., Chewning, J. H., Spellman, S., Haagenson, M., et al. (2012). HLA-C–dependent prevention of leukemia relapse by donor activating KIR2DS1. New England Journal of Medicine, 367(9), 805–816.

    Article  CAS  Google Scholar 

  113. Alvarez, M., Sun, K., & Murphy, W. J. (2016). Mouse host unlicensed NK cells promote donor allogeneic bone marrow engraftment. Blood, 127(9), 1202–1205.

    Article  CAS  Google Scholar 

  114. Olson, J. A., Leveson-Gower, D. B., Gill, S., Baker, J., Beilhack, A., & Negrin, R. S. (2010). NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects. Blood, 115(21), 4293–4301.

    Article  CAS  Google Scholar 

  115. Ruggeri, L., Capanni, M., Urbani, E., Perruccio, K., Shlomchik, W. D., Tosti, A., et al. (2002). Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science, 295(5562), 2097–2100.

    Article  CAS  Google Scholar 

  116. Simonetta, F., Alvarez, M., & Negrin, R. S. (2017). Natural killer cells in graft-versus-host-disease after allogeneic hematopoietic cell transplantation. Frontiers in Immunology, 8, 465.

    Article  Google Scholar 

  117. Bunting, M. D., Varelias, A., Souza-Fonseca-Guimaraes, F., Schuster, I. S., Lineburg, K. E., Kuns, R. D., et al. (2017). GVHD prevents NK-cell–dependent leukemia and virus-specific innate immunity. Blood the Journal of the American Society of Hematology, 129(5), 630–642.

    CAS  Google Scholar 

  118. Nguyen, S., Kuentz, M., Vernant, J., Dhedin, N., Bories, D., Debre, P., et al. (2008). Involvement of mature donor T cells in the NK cell reconstitution after haploidentical hematopoietic stem-cell transplantation. Leukemia, 22(2), 344–352.

    Article  CAS  Google Scholar 

  119. Caligiuri, M. A. (2008). Human natural killer cells. Blood. The Journal of the American Society of Hematology, 112(3), 461–469.

    CAS  Google Scholar 

  120. Marcenaro, E., Cantoni, C., Pesce, S., Prato, C., Pende, D., Agaugué, S., et al. (2009). Uptake of CCR7 and acquisition of migratory properties by human KIR + NK cells interacting with monocyte-derived DC or EBV cell lines: regulation by KIR/HLA-class I interaction. Blood the Journal of the American Society of Hematology, 114(19), 4108–4116.

    CAS  Google Scholar 

  121. Trivedi, P. P., Roberts, P. C., Wolf, N. A., & Swanborg, R. H. (2005). NK cells inhibit T cell proliferation via p21-mediated cell cycle arrest. The Journal of Immunology, 174(8), 4590–4597.

    Article  CAS  Google Scholar 

  122. Cerboni, C., Zingoni, A., Cippitelli, M., Piccoli, M., Frati, L., & Santoni, A. (2007). Antigen-activated human T lymphocytes express cell-surface NKG2D ligands via an ATM/ATR-dependent mechanism and become susceptible to autologous NK-cell lysis. Blood, 110(2), 606–615.

    Article  CAS  Google Scholar 

  123. Rabinovich, B. A., Li, J., Shannon, J., Hurren, R., Chalupny, J., Cosman, D., et al. (2003). Activated, but not resting, T cells can be recognized and killed by syngeneic NK cells. The Journal of Immunology, 170(7), 3572–3576.

    Article  CAS  Google Scholar 

  124. Ghadially, H., Ohana, M., Elboim, M., Gazit, R., Gur, C., Nagler, A., et al. (2014). NK cell receptor NKp46 regulates graft-versus-host disease. Cell Reports, 7(6), 1809–1814.

    Article  CAS  Google Scholar 

  125. Venstrom, J. M., Gooley, T. A., Spellman, S., Pring, J., Malkki, M., Dupont, B., et al. (2010). Donor activating KIR3DS1 is associated with decreased acute GVHD in unrelated allogeneic hematopoietic stem cell transplantation. Blood the Journal of the American Society of Hematology, 115(15), 3162–3165.

    CAS  Google Scholar 

  126. Huntington, N. D. (2014). The unconventional expression of IL-15 and its role in NK cell homeostasis. Immunology and Cell Biology, 92(3), 210–213.

    Article  CAS  Google Scholar 

  127. Meguro, A., Ozaki, K., Oh, I., Hatanaka, K., Matsu, H., Tatara, R., et al. (2010). IL-21 is critical for GVHD in a mouse model. Bone Marrow Transplantation, 45(4), 723–729.

    Article  CAS  Google Scholar 

  128. Pratt, L., Liu, Y., Ugarte-Torres, A., Hoegh-Petersen, M., Podgorny, P., Lyon, A., et al. (2013). IL15 levels on day 7 after hematopoietic cell transplantation predict chronic GVHD. Bone Marrow Transplantation, 48(5), 722–728.

    Article  CAS  Google Scholar 

  129. Chan, Y. L. T., Zuo, J., Inman, C., Croft, W., Begum, J., Croudace, J., et al. (2018). NK cells produce high levels of IL-10 early after allogeneic stem cell transplantation and suppress development of acute GVHD. European Journal of Immunology, 48(2), 316–329.

    Article  CAS  Google Scholar 

  130. Hu, L. J., Zhao, X. Y., Yu, X. X., Lv, M., Han, T. T., Han, W., et al. (2019). Quantity and quality reconstitution of NKG2A + natural killer cells are associated with graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biology of Blood and Marrow Transplantation, 25(1), 1–11.

    Article  Google Scholar 

  131. Bao, X., Hou, L., Sun, A., Qiu, Q., Yuan, X., Chen, M., et al. (2010). The impact of KIR2DS4 alleles and the expression of KIR in the development of acute GVHD after unrelated allogeneic hematopoietic SCT. Bone Marrow Transplantation, 45(9), 1435–1441.

    Article  CAS  Google Scholar 

  132. Hosokai, R., Masuko, M., Shibasaki, Y., Saitoh, A., Furukawa, T., & Imai, C. (2017). Donor killer immunoglobulin-like receptor haplotype B/x induces severe acute graft-versus-host disease in the presence of human leukocyte antigen mismatch in T cell–replete hematopoietic cell transplantation. Biology of Blood and Marrow Transplantation, 23(4), 606–611.

    Article  CAS  Google Scholar 

  133. Nishimura, R., Baker, J., Beilhack, A., Zeiser, R., Olson, J. A., Sega, E. I., et al. (2008). In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity. Blood the Journal of the American Society of Hematology, 112(6), 2563–2574.

    CAS  Google Scholar 

  134. Olson, J. A., Zeiser, R., Beilhack, A., Goldman, J. J., & Negrin, R. S. (2009). Tissue-specific homing and expansion of donor NK cells in allogeneic bone marrow transplantation. The Journal of Immunology, 183(5), 3219–3228.

    Article  CAS  Google Scholar 

  135. Zhang, P., Yang, S., Zou, Y., Yan, X., Wu, H., Zhou, M., et al. (2019). NK cell predicts the severity of acute graft-versus-host disease in patients after allogeneic stem cell transplantation using antithymocyte globulin (ATG) in pretreatment scheme. BMC Immunology, 20(1), 46.

    Article  Google Scholar 

  136. Mehta, R. S., Saliba, R. M., Chen, J., Rondon, G., Hammerstrom, A. E., Alousi, A., et al. (2016). Post-transplantation cyclophosphamide versus conventional graft‐versus‐host disease prophylaxis in mismatched unrelated donor haematopoietic cell transplantation. British Journal of Haematology, 173(3), 444–455.

    Article  CAS  Google Scholar 

  137. Scholl, S., Mügge, L., Issa, M. C., Kasper, C., Pachmann, K., Höffken, K., et al. (2005). Impact of early NK cell recovery on development of GvHD and CMV reactivation in dose-reduced regimen prior to allogeneic PBSCT. Bone Marrow Transplantation, 35(2), 183–190.

    Article  CAS  Google Scholar 

  138. Huang, X., Zhao, X., Liu, D., Liu, K., & Xu, L. (2007). Deleterious effects of KIR ligand incompatibility on clinical outcomes in haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion. Leukemia, 21(4), 848–851.

    Article  CAS  Google Scholar 

  139. Lundqvist, A., Philip McCoy, J., Samsel, L., & Childs, R. (2007). Reduction of GVHD and enhanced antitumor effects after adoptive infusion of alloreactive Ly49-mismatched NK cells from MHC-matched donors. Blood, 109(8), 3603–3606.

    Article  CAS  Google Scholar 

  140. Asai, O., Longo, D. L., Tian, Z. G., Hornung, R. L., Taub, D. D., Ruscetti, F. W., et al. (1998). Suppression of graft-versus-host disease and amplification of graft-versus-tumor effects by activated natural killer cells after allogeneic bone marrow transplantation. The Journal of Clinical Investigation, 101(9), 1835–1842.

    Article  CAS  Google Scholar 

  141. Yang, Y. G., Dey, B. R., Sergio, J. J., Pearson, D. A., & Sykes, M. (1998). Donor-derived interferon gamma is required for inhibition of acute graft-versus-host disease by interleukin 12. The Journal of Clinical Investigation, 102(12), 2126–2135.

    Article  CAS  Google Scholar 

  142. Sweeney, C., & Vyas, P. (2019). The graft-versus-leukemia effect in AML. Frontiers in Oncology, 9, 1217.

  143. Lanier, L. L. (2005). NK cell recognition. Annual Review of Immunology, 23, 225–274.

    Article  CAS  Google Scholar 

  144. Aversa, F., Tabilio, A., Terenzi, A., Velardi, A., Falzetti, F., Giannoni, C., Iacucci, R., Zei, T., Martelli, M. P., & Gambelunghe, C. (1994). Successful engraftment of T-cell-depleted haploidentical “three-loci” incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum. Blood, 84(11), 3948–3955.

    Article  CAS  Google Scholar 

  145. Locatelli, F., Pende, D., Falco, M., Della Chiesa, M., Moretta, A., & Moretta, L. (2018). NK cells mediate a crucial graft-versus-leukemia effect in haploidentical-HSCT to cure high-risk acute leukemia. Trends in Immunology, 39(7), 577–590.

    Article  CAS  Google Scholar 

  146. Arvindam, U. S., Aguilar, E. G., Felices, M., Murphy, W., & Miller, J. (2019). Natural Killer Cells in GvHD and GvL. Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation (pp. 275–292). Elsevier.

  147. Retiere, C., Willem, C., Legrand, N., Guillaume, T., Gagne, K., Peterlin, P., et al. (2017). NK-cell alloreactivity is associated with acute Gvhd and decreased relapse incidence after T-replete haplo-identical allotransplant with high-dose post-transplant cyclophosphamide. Blood, 130(Supplement 1), 3262.

    Google Scholar 

  148. Willem, C., Makanga, D. R., Guillaume, T., Maniangou, B., Legrand, N., Gagne, K., et al. (2019). Impact of KIR/HLA incompatibilities on NK cell reconstitution and clinical outcome after T Cell–replete haploidentical hematopoietic stem cell transplantation with posttransplant cyclophosphamide. The Journal of Immunology, 202(7), 2141–2152.

    Article  CAS  Google Scholar 

  149. Ruggeri, L., Mancusi, A., Capanni, M., Urbani, E., Carotti, A., Aloisi, T., et al. (2007). Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value. Blood, 110(1), 433–440.

    Article  CAS  Google Scholar 

  150. Luznik, L., O’Donnell, P. V., & Fuchs, E. J. (Eds.). (2012). Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Seminars in oncology. Elsevier.

  151. Shimoni, A., Labopin, M., Lorentino, F., Van Lint, M. T., Koc, Y., Gülbas, Z., et al. (2019). Killer cell immunoglobulin-like receptor ligand mismatching and outcome after haploidentical transplantation with post-transplant cyclophosphamide. Leukemia, 33(1), 230–239.

    Article  CAS  Google Scholar 

  152. Hsu, K. C., Gooley, T., Malkki, M., Pinto-Agnello, C., Dupont, B., Bignon, J. D., et al. (2006). KIR ligands and prediction of relapse after unrelated donor hematopoietic cell transplantation for hematologic malignancy. Biology of Blood and Marrow Transplantation, 12(8), 828–836.

    Article  CAS  Google Scholar 

  153. Hsu, K. C., Keever-Taylor, C. A., Wilton, A., Pinto, C., Heller, G., Arkun, K., et al. (2005). Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes. Blood, 105(12), 4878–4884.

    Article  CAS  Google Scholar 

  154. Shaffer, B. C., & Hsu, K. C. (2016). How important is NK alloreactivity and KIR in allogeneic transplantation? Best Practice & Research Clinical Haematology, 29(4), 351–358.

    Article  Google Scholar 

  155. Faridi, R. M., Kemp, T. J., Dharmani-Khan, P., Lewis, V., Tripathi, G., Rajalingam, R., et al. (2016). Donor-recipient matching for KIR genotypes reduces chronic GVHD and missing inhibitory KIR ligands protect against relapse after myeloablative, HLA matched hematopoietic cell transplantation. PLoS One, 11(6), e0158242.

    Article  Google Scholar 

  156. Russo, A., Oliveira, G., Berglund, S., Greco, R., Gambacorta, V., Cieri, N., et al. (2018). NK cell recovery after haploidentical HSCT with posttransplant cyclophosphamide: dynamics and clinical implications. Blood the Journal of the American Society of Hematology, 131(2), 247–262.

    CAS  Google Scholar 

  157. Wolschke, C., Stübig, T., Hegenbart, U., Schönland, S., Heinzelmann, M., Hildebrandt, Y., et al. (2013). Postallograft lenalidomide induces strong NK cell–mediated antimyeloma activity and risk for T cell–mediated GvHD: Results from a phase I/II dose-finding study. Experimental Hematology, 41(2), 134–142. e3.

    Article  CAS  Google Scholar 

  158. Kheav, V. D., Busson, M., Scieux, C., de Latour, R. P., Maki, G., Haas, P., et al. (2014). Favorable impact of natural killer cell reconstitution on chronic graft-versus-host disease and cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation. Haematologica, 99(12), 1860–1867.

    Article  CAS  Google Scholar 

  159. Liu, L. L., Béziat, V., Oei, V. Y., Pfefferle, A., Schaffer, M., Lehmann, S., et al. (2017). Ex vivo expanded adaptive NK cells effectively kill primary acute lymphoblastic leukemia cells. Cancer Immunology Research, 5(8), 654–665.

    Article  CAS  Google Scholar 

  160. Sánchez-Martínez, D., Lanuza, P. M., Gómez, N., Muntasell, A., Cisneros, E., Moraru, M., et al. (2016). Activated allogeneic NK cells preferentially kill poor prognosis B-cell chronic lymphocytic leukemia cells. Frontiers in Immunology, 7, 454.

    Article  Google Scholar 

  161. Torelli, G. F., Peragine, N., Raponi, S., Pagliara, D., De Propris, M. S., Vitale, A., et al. (2014). Recognition of adult and pediatric acute lymphoblastic leukemia blasts by natural killer cells. Haematologica, 99(7), 1248–1254.

    Article  Google Scholar 

  162. Ureshino, H., Shindo, T., Sano, H., Kubota, Y., Ando, T., Kidoguchi, K., Kusaba, K., Itamura, H., Kojima, H., Kusunoki, Y., Miyazaki, Y., Kojima, K., Tanaka, H., Saji, H., Oshima, K., & Kimura, S. (2020). Reconstitution of NK cells expressing KIR3DL1 is associated with reduced NK cell activity and relapse of CML after allogeneic hematopoietic stem cell transplantation. International Journal of Hematology, 111(5), 733–738. https://doi.org/10.1007/s12185-019-02809-5

    Article  CAS  Google Scholar 

  163. Mancusi, A., Ruggeri, L., Urbani, E., Pierini, A., Massei, M. S., Carotti, A., et al. (2015). Haploidentical hematopoietic transplantation from KIR ligand–mismatched donors with activating KIRs reduces nonrelapse mortality. Blood, 125(20), 3173–3182.

    Article  CAS  Google Scholar 

  164. Marcenaro, E., Carlomagno, S., Pesce, S., Della Chiesa, M., Moretta, A., & Sivori, S. (2011). Role of alloreactive KIR2DS1 + NK cells in haploidentical hematopoietic stem cell transplantation. Journal of Leukocyte Biology, 90(4), 661–667.

    Article  CAS  Google Scholar 

  165. Hu, B., He, Y., Wu, Y., Bao, G., Liu, H., Welniak, L. A., et al. (2010). Activated allogeneic NK cells as suppressors of alloreactive responses. Biology of Blood and Marrow Transplantation, 16(6), 772–781.

    Article  CAS  Google Scholar 

  166. Wang, H., & Yang, Y. G. (2014). The complex and central role of interferon-γ in graft‐versus‐host disease and graft‐versus‐tumor activity. Immunological Reviews, 258(1), 30–44.

    Article  CAS  Google Scholar 

  167. Yang, Y. G., Qi, J., Wang, M. G., & Sykes, M. (2002). Donor-derived interferon γ separates graft-versus-leukemia effects and graft-versus-host disease induced by donor CD8 T cells. Blood the Journal of the American Society of Hematology, 99(11), 4207–4215.

    CAS  Google Scholar 

  168. Gill, S., Vasey, A. E., De Souza, A., Baker, J., Smith, A. T., Kohrt, H. E., et al. (2012). Rapid development of exhaustion and down-regulation of eomesodermin limit the antitumor activity of adoptively transferred murine natural killer cells. Blood, 119(24), 5758–5768.

    Article  CAS  Google Scholar 

  169. Simonetta, F., Pradier, A., Bosshard, C., Masouridi-Levrat, S., Chalandon, Y., & Roosnek, E. (2015). NK cell functional impairment after allogeneic hematopoietic stem cell transplantation is associated with reduced levels of T-bet and eomesodermin. The Journal of Immunology, 195(10), 4712–4720.

    Article  CAS  Google Scholar 

  170. Wagner, J. A., Wong, P., Schappe, T., Berrien-Elliott, M. M., Cubitt, C., Jaeger, N., et al. (2020). Stage-Specific Requirement for Eomes in Mature NK Cell Homeostasis and Cytotoxicity. Cell Reports, 31(9), 107720.

    Article  CAS  Google Scholar 

  171. Ghasemzadeh, M., Hosseini, E., Schwarer, A. P., & Pourfathollah, A. A. (2016). NK cell maturation to CD56dim subset associated with high levels of NCRs overrides the inhibitory effect of NKG2A and recovers impaired NK cell cytolytic potential after allogeneic hematopoietic stem cell transplantation. Leukemia Research, 43, 58–65.

    Article  CAS  Google Scholar 

  172. Grzywacz, B., Kataria, N., Sikora, M., Oostendorp, R. A., Dzierzak, E. A., Blazar, B. R., et al. (2006). Coordinated acquisition of inhibitory and activating receptors and functional properties by developing human natural killer cells. Blood, 108(12), 3824–3833.

    Article  CAS  Google Scholar 

  173. Minculescu, L., Marquart, H. V., Friis, L. S., Petersen, S. L., Schiødt, I., Ryder, L. P., Andersen, N. S., & Sengeloev, H. (2016). Early natural killer cell reconstitution predicts overall survival in T cell-replete allogeneic hematopoietic stem cell transplantation. Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, 22(12), 2187–2193. https://doi.org/10.1016/j.bbmt.2016.09.006

    Article  CAS  Google Scholar 

  174. Minculescu, L., Fischer-Nielsen, A., Haastrup, E., Ryder, L. P., Andersen, N. S., Schjoedt, I., et al. (2020). Improved relapse-free survival in patients with high natural killer cell doses in grafts and during early immune reconstitution after allogeneic stem cell transplantation. Frontiers in Immunology, 11, 1068.

    Article  CAS  Google Scholar 

  175. Hu, L., Zhao, X. Y., Yu, X., Lv, M., Han, T. T., Han, W., et al. (2018). Quantity and quality reconstitution of NKG2A + NK cells are associated with graft-versus-host disease after allogeneic hematopoietic cell transplantation. Blood, 132(Supplement 1), 4582.

    Article  Google Scholar 

  176. Lang, P., Feuchtinger, T., Teltschik, H., Schwinger, W., Schlegel, P., Pfeiffer, M., et al. (2015). Improved immune recovery after transplantation of TCRαβ/CD19-depleted allografts from haploidentical donors in pediatric patients. Bone Marrow Transplantation, 50(2), S6–S10.

    Article  CAS  Google Scholar 

  177. Locatelli, F., Merli, P., Pagliara, D., Li Pira, G., Falco, M., Pende, D., et al. (2017). Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion. Blood, 130(5), 677–685.

    Article  CAS  Google Scholar 

  178. Merli, P., Vacca, P., Galaverna, F., Tumino, N., Moretta, L., & Locatelli, F. (2020). TCRαβ/CD19 depleted hematopoietic stem cell transplantation from haploidentical donors: Dissecting the GvL/GvHD conundrum. Bone Marrow Transplantation, 55(7), 1483–1484. https://doi.org/10.1038/s41409-020-0891-8

    Article  Google Scholar 

  179. Ciurea, S. O., Schafer, J. R., Bassett, R., Denman, C. J., Cao, K., Willis, D., et al. (2017). Phase 1 clinical trial using mbIL21 ex vivo–expanded donor-derived NK cells after haploidentical transplantation. Blood, 130(16), 1857–1868.

    Article  CAS  Google Scholar 

  180. Leong, J. W., Chase, J. M., Romee, R., Schneider, S. E., Sullivan, R. P., Cooper, M. A., et al. (2014). Preactivation with IL-12, IL-15, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cells. Biology of Blood and Marrow Transplantation, 20(4), 463–473.

    Article  CAS  Google Scholar 

  181. Romee, R., Cooley, S., Berrien-Elliott, M. M., Westervelt, P., Verneris, M. R., Wagner, J. E., et al. (2018). First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood, 131(23), 2515–2527.

    Article  CAS  Google Scholar 

  182. Song, Y., Hu, B., Liu, Y., Jin, Z., Zhang, Y., Lin, D., et al. (2018). IL-12/IL‐18‐preactivated donor NK cells enhance GVL effects and mitigate GvHD after allogeneic hematopoietic stem cell transplantation. European Journal of Immunology, 48(4), 670–682.

    Article  CAS  Google Scholar 

  183. Davids, M. S., Kim, H. T., Bachireddy, P., Costello, C., Liguori, R., Savell, A., et al. (2016). Ipilimumab for patients with relapse after allogeneic transplantation. New England Journal Of Medicine, 375, 143–153.

    Article  CAS  Google Scholar 

  184. Hattori, N., & Nakamaki, T. (2019). Natural killer immunotherapy for minimal residual disease eradication following allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia. International Journal of Molecular Sciences, 20(9), 2057.

    Article  CAS  Google Scholar 

  185. Hsu, J., Hodgins, J. J., Marathe, M., Nicolai, C. J., Bourgeois-Daigneault, M. C., Trevino, T. N., et al. (2018). Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. The Journal of Clinical Investigation, 128(10), 4654–4668.

    Article  Google Scholar 

  186. Korde, N., Carlsten, M., Lee, M. J., Minter, A., Tan, E., Kwok, M., et al. (2014). A phase II trial of pan-KIR2D blockade with IPH2101 in smoldering multiple myeloma. Haematologica, 99(6), e81.

    Article  CAS  Google Scholar 

  187. Sivori, S., Vacca, P., Del Zotto, G., Munari, E., Mingari, M. C., & Moretta, L. (2019). Human NK cells: surface receptors, inhibitory checkpoints, and translational applications. Cellular & Molecular Immunology, 16(5), 430–441.

    Article  CAS  Google Scholar 

  188. Gleason, M. K., Verneris, M. R., Todhunter, D. A., Zhang, B., McCullar, V., Zhou, S. X., et al. (2012). Bispecific and trispecific killer cell engagers directly activate human NK cells through CD16 signaling and induce cytotoxicity and cytokine production. Molecular Cancer Therapeutics, 11(12), 2674–2684.

    Article  CAS  Google Scholar 

  189. Gonzalez-Rodriguez, A. P., Villa-Álvarez, M., Sordo-Bahamonde, C., Lorenzo-Herrero, S., & Gonzalez, S. (2019). NK cells in the treatment of hematological malignancies. Journal of Clinical Medicine, 8(10), 1557.

    Article  CAS  Google Scholar 

  190. Rader, C. (2020). Bispecific antibodies in cancer immunotherapy. Current Opinion in Biotechnology, 65, 9–16.

    Article  CAS  Google Scholar 

  191. Tanaka, J., & Miller, J. S. (2020). Recent progress in and challenges in cellular therapy using NK cells for hematological malignancies. Blood Reviews, 44, 100678. https://doi.org/10.1016/j.blre.2020.100678

    Article  CAS  Google Scholar 

  192. Lee, D. A., Denman, C. J., Rondon, G., Woodworth, G., Chen, J., Fisher, T., et al. (2016). Haploidentical natural killer cells infused before allogeneic stem cell transplantation for myeloid malignancies: a phase I trial. Biology of Blood and Marrow Transplantation, 22(7), 1290–1298.

    Article  CAS  Google Scholar 

  193. Hu, Y., Tian, Z., & Zhang, C. (2018). Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy. Acta Pharmacologica Sinica, 39(2), 167–176.

    Article  CAS  Google Scholar 

  194. Vacca, P., Pietra, G., Tumino, N., Munari, E., Mingari, M. C., & Moretta, L. (2020). Exploiting human NK cells in tumor therapy. Frontiers in Immunology, 10, 3013.

    Article  Google Scholar 

  195. Boyiadzis, M., Hong, C. S., & Whiteside, T. L. (2019). Anti-leukemia effects of NK cell-derived exosomes. Blood, 134, 3223.

    Article  Google Scholar 

  196. Samara, A., Granot, G., Anbar, M., Raanani, P., & Rozovski, U. (2021). Using NK-derived exosomes to treat leukemia. Blood, 138, 1872.

    Article  Google Scholar 

  197. Lieberman, J. (2010). Granzyme A activates another way to die. Immunological Reviews, 235(1), 93–104.

    Article  CAS  Google Scholar 

  198. MacDonald, G., Shi, L., Velde, C. V., Lieberman, J., & Greenberg, A. H. (1999). Mitochondria-dependent and-independent regulation of granzyme B–induced apoptosis. The Journal of Experimental Medicine, 189(1), 131–144.

    Article  CAS  Google Scholar 

  199. Sun, H., Shi, K., Qi, K., Kong, H., Zhang, J., Dai, S., Ye, W., Deng, T., He, Q., & Zhou, M. (2019). Natural killer cell-derived exosomal miR-3607-3p inhibits pancreatic cancer progression by targeting IL-26. Frontiers in Immunology, 10, 2819. https://doi.org/10.3389/fimmu.2019.02819

    Article  CAS  Google Scholar 

  200. Chen, K., Cheng, M. P., Hammond, S. P., Einsele, H., & Marty, F. M. (2018). Antiviral prophylaxis for cytomegalovirus infection in allogeneic hematopoietic cell transplantation. Blood Advances, 2(16), 2159–2175.

    Article  CAS  Google Scholar 

  201. GriffithsP, B., & ReevesM. (2015). The pathogenesis of human cytomegalovirus. The Journal of Pathology, 235(2), 288–297.

    Article  Google Scholar 

  202. Camargo, J. F., & Komanduri, K. V. (2017). Emerging concepts in cytomegalovirus infection following hematopoietic stem cell transplantation. Hematology/Oncology and Stem Cell Therapy, 10(4), 233–238.

    Article  CAS  Google Scholar 

  203. Foley, B., Cooley, S., Verneris, M. R., Pitt, M., Curtsinger, J., Luo, X., et al. (2012). Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C + natural killer cells with potent function. Blood, 119(11), 2665–2674.

    Article  CAS  Google Scholar 

  204. Cichocki, F., Taras, E., Chiuppesi, F., Wagner, J. E., Blazar, B. R., Brunstein, C., Luo, X., Diamond, D. J., Cooley, S., Weisdorf, D. J., & Miller, J. S. (2019). Adaptive NK cell reconstitution is associated with better clinical outcomes. JCI Insight, 4(2), e125553. https://doi.org/10.1172/jci.insight.125553

    Article  Google Scholar 

  205. Sun, J. C., Beilke, J. N., & Lanier, L. L. (2009). Adaptive immune features of natural killer cells. Nature, 457(7229), 557–561.

    Article  CAS  Google Scholar 

  206. Cichocki, F., Cooley, S., Davis, Z., DeFor, T. E., Schlums, H., Zhang, B., et al. (2016). CD56 dim CD57 + NKG2C + NK cell expansion is associated with reduced leukemia relapse after reduced intensity HCT. Leukemia, 30(2), 456–463.

    Article  CAS  Google Scholar 

  207. Foley, B., Cooley, S., Verneris, M. R., Curtsinger, J., Luo, X., Waller, E. K., et al. (2012). Human cytomegalovirus (CMV)-induced memory-like NKG2C + NK cells are transplantable and expand in vivo in response to recipient CMV antigen. The Journal of Immunology, 189(10), 5082–5088.

    Article  CAS  Google Scholar 

  208. Muccio, L., Bertaina, A., Falco, M., Pende, D., Meazza, R., Lopez-Botet, M., et al. (2016). Analysis of memory-like natural killer cells in human cytomegalovirus-infected children undergoing αβ + T and B cell-depleted hematopoietic stem cell transplantation for hematological malignancies. Haematologica, 101(3), 371–381.

    Article  CAS  Google Scholar 

  209. Béziat, V., Liu, L. L., Malmberg, J. A., Ivarsson, M. A., Sohlberg, E., Björklund, A. T., et al. (2013). NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs. Blood, 121(14), 2678–2688.

    Article  Google Scholar 

  210. Lopez-Vergès, S., Milush, J. M., Schwartz, B. S., Pando, M. J., Jarjoura, J., York, V. A., et al. (2011). Expansion of a unique CD57 + NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proceedings of the National Academy of Sciences, 108(36), 14725-32.

  211. Bélanger, S., Tu, M. M., Rahim, M. M. A., Mahmoud, A. B., Patel, R., Tai, L. H., et al. (2012). Impaired natural killer cell self-education and “missing-self” responses in Ly49-deficient mice. Blood, 120(3), 592–602.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran

    Alireza Zafarani & Mohammad Reza Amirzargar

  2. Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Mahsa Taghavi-Farahabadi

  3. Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Mohammad Hossein Razizadeh

  4. Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Mansoure Mansouri

  5. Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Mohammad Mahmoudi

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  1. Alireza Zafarani
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Alireza zafarani, Mahsa Taghavi-Farahabadi and Mansoure Mansouri wrote the manuscript, Mohammad Hossein Razizadeh, Mohammad Reza Amirzargar prepared the tables, Mohammad Mahmoudi prepared the figure, supervised the study and correspondence during the paper preparation and submission, RSV read and edited the final submission. The author(s) read and approved the final manuscript.

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Zafarani, A., Taghavi-Farahabadi, M., Razizadeh, M.H. et al. The Role of NK Cells and Their Exosomes in Graft Versus Host Disease and Graft Versus Leukemia. Stem Cell Rev and Rep 19, 26–45 (2023). https://doi.org/10.1007/s12015-022-10449-2

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