Advertisement

Molecular Programming of Immunological Memory in Natural Killer Cells

  • Aimee M. Beaulieu
  • Sharline Madera
  • Joseph C. Sun
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 850)

Abstract

Immunological memory is a hallmark of the adaptive immune system. Although natural killer (NK) cells have traditionally been classified as a component of the innate immune system, they have recently been shown in mice and humans to exhibit certain features of immunological memory, including an ability to undergo a clonal-like expansion during virus infection, generate long-lived progeny (i.e. memory cells), and mediate recall responses against previously encountered pathogens—all characteristics previously ascribed only to adaptive immune responses by B and T cells in mammals. To date, the molecular events that govern the generation of NK cell memory are not completely understood. Using a mouse model of cytomegalovirus infection, we demonstrate that individual pro-inflammatory IL-12, IL-18, and type I-IFN signaling pathways are indispensible and play non-redundant roles in the generation of virus-specific NK cell memory. Furthermore, we discovered that antigen-specific proliferation and protection by NK cells is mediated by the transcription factor Zbtb32, which is induced by pro-inflammatory cytokines and promotes a cell cycle program in activated NK cells. A greater understanding of the molecular mechanisms controlling NK cell responses will provide novel strategies for tailoring vaccines to target infectious disease.

Keywords

Adaptive immune system Innate immune system NK cell memory Cytokine stimulation 

References

  1. Alonzo, E. S., Gottschalk, R. A., Das, J., Egawa, T., Hobbs, R. M., Pandolfi, P. P., Pereira, P., Nichols, K. E., Koretzky, G. A., Jordan, M. S., et al. (2010). Development of promyelocytic zinc finger and ThPOK-expressing innate gamma delta T cells is controlled by strength of TCR signaling and Id3. Journal of Immunology, 184, 1268–1279.CrossRefGoogle Scholar
  2. Andrews, D. M., Scalzo, A. A., Yokoyama, W. M., Smyth, M. J., & Degli-Esposti, M. A. (2003). Functional interactions between dendritic cells and NK cells during viral infection. Nature Immunology, 4, 175–181.CrossRefPubMedGoogle Scholar
  3. Arase, H., Mocarski, E. S., Campbell, A. E., Hill, A. B., & Lanier, L. L. (2002). Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science, 296, 1323–1326.CrossRefPubMedGoogle Scholar
  4. Beaulieu, A. M., Zawislak, C. L., Nakayama, T., & Sun, J. C. (2014). The transcription factor Zbtb32 controls the proliferative burst of virus-specific natural killer cells responding to infection. Nature Immunology, 15, 546–553.PubMedCentralCrossRefPubMedGoogle Scholar
  5. Bezman, N. A., Kim, C. C., Sun, J. C., Min-Oo, G., Hendricks, D. W., Kamimura, Y., Best, J. A., Goldrath, A. W., & Lanier, L. L. (2012). Molecular definition of the identity and activation of natural killer cells. Nature Immunology, 13, 1000–1009.PubMedCentralCrossRefPubMedGoogle Scholar
  6. Bjorkstrom, N. K., Lindgren, T., Stoltz, M., Fauriat, C., Braun, M., Evander, M., Michaelsson, J., Malmberg, K. J., Klingstrom, J., Ahlm, C., et al. (2011). Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus. The Journal of Experimental Medicine, 208, 13–21.PubMedCentralCrossRefPubMedGoogle Scholar
  7. Cooper, M. A., Elliott, J. M., Keyel, P. A., Yang, L., Carrero, J. A., & 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.PubMedCentralCrossRefPubMedGoogle Scholar
  8. Della Chiesa, M., Falco, M., Podesta, M., Locatelli, F., Moretta, L., Frassoni, F., & Moretta, A. (2012). Phenotypic and functional heterogeneity of human NK cells developing after umbilical cord blood transplantation: A role for human cytomegalovirus? Blood, 119, 399–410.CrossRefPubMedGoogle Scholar
  9. Dent, A. L., Shaffer, A. L., Yu, X., Allman, D., & Staudt, L. M. (1997). Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science, 276, 589–592.CrossRefPubMedGoogle Scholar
  10. Foley, B., Cooley, S., Verneris, M. R., Curtsinger, J., Luo, X., Waller, E. K., Anasetti, C., Weisdorf, D., & Miller, J. S. (2012a). 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.CrossRefGoogle Scholar
  11. Foley, B., Cooley, S., Verneris, M. R., Pitt, M., Curtsinger, J., Luo, X., Lopez-Verges, S., Lanier, L. L., Weisdorf, D., & Miller, J. S. (2012b). Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C + natural killer cells with potent function. Blood, 119, 2665–2674.PubMedCentralCrossRefPubMedGoogle Scholar
  12. Guma, M., Budt, M., Saez, A., Brckalo, T., Hengel, H., Angulo, A., & Lopez-Botet, M. (2006). Expansion of CD94/NKG2C+ NK cells in response to human cytomegalovirus-infected fibroblasts. Blood, 107, 3624–3631.CrossRefPubMedGoogle Scholar
  13. He, X., He, X., Dave, V. P., Zhang, Y., Hua, X., Nicolas, E., Xu, W., Roe, B. A., & Kappes, D. J. (2005). The zinc finger transcription factor Th-POK regulates CD4 versus CD8 T-cell lineage commitment. Nature, 433, 826–833.CrossRefPubMedGoogle Scholar
  14. Hirahara, K., Yamashita, M., Iwamura, C., Shinoda, K., Hasegawa, A., Yoshizawa, H., Koseki, H., Gejyo, F., & Nakayama, T. (2008). Repressor of GATA regulates TH2-driven allergic airway inflammation and airway hyperresponsiveness. The Journal of allergy and clinical immunology, 122, 512–520, e511.CrossRefPubMedGoogle Scholar
  15. Hirasaki, Y., Iwamura, C., Yamashita, M., Ito, T., Kitajima, M., Shinoda, K., Namiki, T., Terasawa, K., & Nakayama, T. (2011). Repressor of GATA negatively regulates murine contact hypersensitivity through the inhibition of type-2 allergic responses. Clinical Immunology, 139, 267–276.CrossRefPubMedGoogle Scholar
  16. Jamieson, A. M., Isnard, P., Dorfman, J. R., Coles, M. C., & Raulet, D. H. (2004). Turnover and proliferation of NK cells in steady state and lymphopenic conditions. Journal of Immunology, 172, 864–870.CrossRefGoogle Scholar
  17. Johnston, R. J., Poholek, A. C., DiToro, D., Yusuf, I., Eto, D., Barnett, B., Dent, A. L., Craft, J., & Crotty, S. (2009). Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science, 325, 1006–1010.PubMedCentralCrossRefPubMedGoogle Scholar
  18. Keppel, M. P., Yang, L., & Cooper, M. A. (2013). Murine NK cell intrinsic cytokine-induced memory-like responses are maintained following homeostatic proliferation. Journal of Immunology, 190, 4754–4762.CrossRefGoogle Scholar
  19. Kovalovsky, D., Uche, O. U., Eladad, S., Hobbs, R. M., Yi, W., Alonzo, E., Chua, K., Eidson, M., Kim, H. J., Im, J. S., et al. (2008). The BTB-zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions. Nature Immunology, 9, 1055–1064.PubMedCentralCrossRefPubMedGoogle Scholar
  20. Kreslavsky, T., Savage, A. K., Hobbs, R., Gounari, F., Bronson, R., Pereira, P., Pandolfi, P. P., Bendelac, A., & von Boehmer, H. (2009). TCR-inducible PLZF transcription factor required for innate phenotype of a subset of gammadelta T cells with restricted TCR diversity. Proceedings of the National Academy of Sciences of the United States of America, 106, 12453–12458.Google Scholar
  21. Lopez-Verges, S., Milush, J. M., Schwartz, B. S., Pando, M. J., Jarjoura, J., York, V. A., Houchins, J. P., Miller, S., Kang, S. M., Norris, P. J., 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 of the United States of America, 108, 14725–14732.PubMedCentralCrossRefPubMedGoogle Scholar
  22. Madera S., & Sun J. C. (2015) Cutting edge: Stage-specific requirement for IL-18 for antiviral NK expansion. Journal of immunology, 194, 1408–1412.Google Scholar
  23. Miaw, S. C., Choi, A., Yu, E., Kishikawa, H., & Ho, I. C. (2000). ROG, repressor of GATA, regulates the expression of cytokine genes. Immunity, 12, 323–333.CrossRefPubMedGoogle Scholar
  24. Min-Oo, G., Bezman, N. A., Madera, S., Sun, J. C., & Lanier, L. L. (2014). Proapoptotic Bim regulates antigen-specific NK cell contraction and the generation of the memory NK cell pool after cytomegalovirus infection. The Journal of Experimental Medicine, 211, 1289–1296.PubMedCentralCrossRefPubMedGoogle Scholar
  25. Muroi, S., Naoe, Y., Miyamoto, C., Akiyama, K., Ikawa, T., Masuda, K., Kawamoto, H., & Taniuchi, I. (2008). Cascading suppression of transcriptional silencers by ThPOK seals helper T cell fate. Nature Immunology, 9, 1113–1121.CrossRefPubMedGoogle Scholar
  26. Nabekura, T., Kanaya, M., Shibuya, A., Fu, G., Gascoigne, N. R., & Lanier, L. L. (2014). Costimulatory molecule DNAM-1 Is essential for optimal differentiation of memory natural killer cells during mouse cytomegalovirus infection. Immunity, 40, 225–234.PubMedCentralCrossRefPubMedGoogle Scholar
  27. Nguyen, K. B., Salazar-Mather, T. P., Dalod, M. Y., Van Deusen, J. B., Wei, X. Q., Liew, F. Y., Caligiuri, M. A., Durbin, J. E., & Biron, C. A. (2002). Coordinated and distinct roles for IFN-alpha beta, IL-12, and IL-15 regulation of NK cell responses to viral infection. Journal of immunology, 169, 4279–4287.CrossRefGoogle Scholar
  28. Ni, J., Miller, M., Stojanovic, A., Garbi, N., & Cerwenka, A. (2012). Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. The Journal of Experimental Medicine, 209, 2351–2365.PubMedCentralCrossRefPubMedGoogle Scholar
  29. Nurieva, R. I., Chung, Y., Martinez, G. J., Yang, X. O., Tanaka, S., Matskevitch, T. D., Wang, Y. H., & Dong, C. (2009). Bcl6 mediates the development of T follicular helper cells. Science, 325, 1001–1005.PubMedCentralCrossRefPubMedGoogle Scholar
  30. O'Leary, J. G., Goodarzi, M., Drayton, D. L., & von Andrian, U. H. (2006). T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nature Immunology, 7, 507–516.CrossRefPubMedGoogle Scholar
  31. Omori, M., Yamashita, M., Inami, M., Ukai-Tadenuma, M., Kimura, M., Nigo, Y., Hosokawa, H., Hasegawa, A., Taniguchi, M., & Nakayama, T. (2003). CD8 T cell-specific downregulation of histone hyperacetylation and gene activation of the IL-4 gene locus by ROG, repressor of GATA. Immunity, 19, 281–294.CrossRefPubMedGoogle Scholar
  32. Orange, J. S., & Biron, C. A. (1996a). An absolute and restricted requirement for IL-12 in natural killer cell IFN-gamma production and antiviral defense. Studies of natural killer and T cell responses in contrasting viral infections. Journal of Immunology, 156, 1138–1142.Google Scholar
  33. Orange, J. S., & Biron, C. A. (1996b). Characterization of early IL-12, IFN-alphabeta, and TNF effects on antiviral state and NK cell responses during murine cytomegalovirus infection. Journal of Immunology, 156, 4746–4756.Google Scholar
  34. 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., et al. (2010). Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses. Nature Immunology, 11, 1127–1135.PubMedCentralCrossRefPubMedGoogle Scholar
  35. Pien, G. C., & Biron, C. A. (2000). Compartmental differences in NK cell responsiveness to IL-12 during lymphocytic choriomeningitis virus infection. Journal of Immunology, 164, 994–1001.CrossRefGoogle Scholar
  36. Prlic, M., Blazar, B. R., Farrar, M. A., & Jameson, S. C. (2003). In vivo survival and homeostatic proliferation of natural killer cells. The Journal of Experimental Medicine, 197, 967–976.PubMedCentralCrossRefPubMedGoogle Scholar
  37. Ranson, T., Vosshenrich, C. A., Corcuff, E., Richard, O., Muller, W., & Di Santo, J. P. (2003). IL-15 is an essential mediator of peripheral NK-cell homeostasis. Blood, 101, 4887–4893.CrossRefPubMedGoogle Scholar
  38. Romee, R., Schneider, S. E., Leong, J. W., Chase, J. M., Keppel, C. R., Sullivan, R. P., Cooper, M. A., & Fehniger, T. A. (2012). Cytokine activation induces human memory-like NK cells. Blood, 120, 4751–4760.PubMedCentralCrossRefPubMedGoogle Scholar
  39. Savage, A. K., Constantinides, M. G., Han, J., Picard, D., Martin, E., Li, B., Lantz, O., & Bendelac, A. (2008). The transcription factor PLZF directs the effector program of the NKT cell lineage. Immunity, 29, 391–403.PubMedCentralCrossRefPubMedGoogle Scholar
  40. Smith, H. R., Heusel, J. W., Mehta, I. K., Kim, S., Dorner, B. G., Naidenko, O. V., Iizuka, K., Furukawa, H., Beckman, D. L., Pingel, J. T., et al. (2002). Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proceedings of the National Academy of Sciences of the United States of America, 99, 8826–8831.Google Scholar
  41. Sun, J. C., & Lanier, L. L. (2011). NK cell development, homeostasis and function: Parallels with CD8(+) T cells. Nature Reviews Immunology, 11, 645–657.PubMedCentralCrossRefPubMedGoogle Scholar
  42. Sun, G., Liu, X., Mercado, P., Jenkinson, S. R., Kypriotou, M., Feigenbaum, L., Galera, P., & Bosselut, R. (2005). The zinc finger protein cKrox directs CD4 lineage differentiation during intrathymic T cell positive selection. Nature Immunology, 6, 373–381.CrossRefPubMedGoogle Scholar
  43. Sun, J. C., Beilke, J. N., & Lanier, L. L. (2009). Adaptive immune features of natural killer cells. Nature, 457, 557–561.PubMedCentralCrossRefPubMedGoogle Scholar
  44. Sun, J. C., Beilke, J. N., Bezman, N. A., & Lanier, L. L. (2011). Homeostatic proliferation generates long-lived natural killer cells that respond against viral infection. The Journal of Experimental Medicine, 208, 357–368.PubMedCentralCrossRefPubMedGoogle Scholar
  45. Sun, J. C., Madera, S., Bezman, N. A., Beilke, J. N., Kaplan, M. H., & Lanier, L. L. (2012). Proinflammatory cytokine signaling required for the generation of natural killer cell memory. The Journal of Experimental Medicine, 209, 947–954.PubMedCentralCrossRefPubMedGoogle Scholar
  46. Ye, B. H., Cattoretti, G., Shen, Q., Zhang, J., Hawe, N., de Waard, R., Leung, C., Nouri-Shirazi, M., Orazi, A., Chaganti, R. S., et al. (1997). The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nature Genetics, 16, 161–170.CrossRefPubMedGoogle Scholar
  47. Yu, D., Rao, S., Tsai, L. M., Lee, S. K., He, Y., Sutcliffe, E. L., Srivastava, M., Linterman, M., Zheng, L., Simpson, N., et al. (2009). The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity, 31, 457–468.CrossRefPubMedGoogle Scholar
  48. Zawislak, C. L., Beaulieu, A. M., Loeb, G. B., Karo, J., Canner, D., Bezman, N. A., Lanier, L. L., Rudensky, A. Y., & Sun, J. C. (2013). Stage-specific regulation of natural killer cell homeostasis and response against viral infection by microRNA-155. Proceedings of the National Academy of Sciences of the United States of America, 110, 6967–6972.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Aimee M. Beaulieu
    • 1
  • Sharline Madera
    • 1
  • Joseph C. Sun
    • 1
  1. 1.Memorial Sloan Kettering Cancer CenterNew YorkUSA

Personalised recommendations