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The Role of Il-12 and Type I Interferon in Governing the Magnitude of CD8 T Cell Responses

  • Gabriel R. Starbeck-MillerEmail author
  • John T. HartyEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 850)

Abstract

Antigen-specific CD8 T cells provide an important protective role in response to infection by viruses, intracellular bacteria, and parasites. Pathogen-specific CD8 T cells render this protection by undergoing robust expansion in numbers while gaining the ability to produce cytokines and cytolytic machinery. Creating optimal CD8 T cell responses to infection can be critical for raising sufficient armament to provide protection against invading intracellular pathogens. Although CD8 T cells have protective value, many vaccine strategies tend to focus on creating productive B cell antibody responses to promote immunological protection. Even though antibody responses can be highly protective, coupling optimal CD8 T cell responses with suboptimal B cell responses could provide higher orders of protection than either one on their own. Therefore, a deeper understanding of the pathways that ultimately guide the magnitude of CD8 T cell responses is required to explore this potential therapeutic benefit. The following chapter highlights our current understanding of how inflammatory cytokines regulate the magnitude of CD8 T cell responses.

Keywords

CD8 T cells Inflammatory cytokines Interleukin-12 Interleukin-2 Type I interferon Signal 3 

References

  1. Acuto, O., & Michel, F. (2003). CD28-mediated co-stimulation: A quantitative support for TCR signalling. Nature Reviews Immunology, 3, 939–951.CrossRefPubMedGoogle Scholar
  2. Aichele, P., Unsoeld, H., Koschella, M., Schweier, O., Kalinke, U., & Vucikuja, S. (2006). CD8 T cells specific for lymphocytic choriomeningitis virus require type I IFN receptor for clonal expansion. Journal of Immunology, 176, 4525–4529.CrossRefGoogle Scholar
  3. Badovinac, V. P., & Harty, J. T. (2006). Programming, demarcating, and manipulating CD8+ T-cell memory. Immunological Reviews, 211, 67–80.CrossRefPubMedGoogle Scholar
  4. Besser, M. J., Shapira-Frommer, R., Treves, A. J., Zippel, D., Itzhaki, O., Hershkovitz, L., Levy, D., Kubi, A., Hovav, E., Chermoshniuk, N., Shalmon, B., Hardan, I., Catane, R., Markel, G., Apter, S., Ben-Nun, A., Kuchuk, I., Shimoni, A., Nagler, A., & Schachter, J. (2010). Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clinical Cancer Research, 16, 2646–2655.CrossRefPubMedGoogle Scholar
  5. Bevan, M. J. (1976). Cross-priming for a secondary cytotoxic response to minor H antigens with H-2 congenic cells which do not cross-react in the cytotoxic assay. Journal of Experimental Medicine, 143, 1283–1288.CrossRefPubMedGoogle Scholar
  6. Boyman, O., & Sprent, J. (2012). The role of interleukin-2 during homeostasis and activation of the immune system. Nature Reviews Immunology, 12, 180–190.PubMedGoogle Scholar
  7. Crompton, J. G., Sukumar, M., & Restifo, N. P. (2014). Uncoupling T-cell expansion from effector differentiation in cell-based immunotherapy. Immunological Reviews, 257, 264–276.PubMedCentralCrossRefPubMedGoogle Scholar
  8. Curtsinger, J. M., Schmidt, C. S., Mondino, A., Lins, D. C., Kedl, R. M., Jenkins, M. K., & Mescher, M. F. (1999). Inflammatory cytokines provide a third signal for activation of naive CD4+ and CD8+ T cells. Journal of Immunology, 162, 3256–3262.Google Scholar
  9. Curtsinger, J. M., Valenzuela, J. O., Agarwal, P., Lins, D., & Mescher, M. F. (2005). Type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. Journal of Immunology, 174, 4465–4469.CrossRefGoogle Scholar
  10. Gately, M. K., Wolitzky, A. G., Quinn, P. M., & Chizzonite, R. (1992). Regulation of human cytolytic lymphocyte responses by interleukin-12. Cellular Immunology, 143, 127–142.CrossRefPubMedGoogle Scholar
  11. Gately, M. K., Warrier, R. R., Honasoge, S., Carvajal, D. M., Faherty, D. A., Connaughton, S. E., Anderson, T. D., Sarmiento, U., Hubbard, B. R., & Murphy, M. (1994). Administration of recombinant IL-12 to normal mice enhances cytolytic lymphocyte activity and induces production of IFN-gamma in vivo. International Immunology, 6, 157–167.CrossRefPubMedGoogle Scholar
  12. Gil, M. P., Ploquin, M. J., Watford, W. T., Lee, S. H., Kim, K., Wang, X., Kanno, Y., O’shea, J. J., & Biron, C. A. (2012). Regulating type 1 IFN effects in CD8 T cells during viral infections: Changing STAT4 and STAT1 expression for function. Blood, 120, 3718–3728.PubMedCentralCrossRefPubMedGoogle Scholar
  13. Guermonprez, P., Saveanu, L., Kleijmeer, M., Davoust, J., Van Endert, P., & Amigorena, S. (2003). ER-phagosome fusion defines an MHC class I cross-presentation compartment in dendritic cells. Nature, 425, 397–402.CrossRefPubMedGoogle Scholar
  14. Harty, J. T., & Badovinac, V. P. (2008). Shaping and reshaping CD8+ T-cell memory. Nature Reviews Immunology, 8, 107–119.CrossRefPubMedGoogle Scholar
  15. Houde, M., Bertholet, S., Gagnon, E., Brunet, S., Goyette, G., Laplante, A., Princiotta, M. F., Thibault, P., Sacks, D., & Desjardins, M. (2003). Phagosomes are competent organelles for antigen cross-presentation. Nature, 425, 402–406.CrossRefPubMedGoogle Scholar
  16. Joffre, O. P., Segura, E., Savina, A., & Amigorena, S. (2012). Cross-presentation by dendritic cells. Nature Reviews Immunology, 12, 557–569.CrossRefPubMedGoogle Scholar
  17. Kaech, S. M., Wherry, E. J., & Ahmed, R. (2002). Effector and memory T-cell differentiation: Implications for vaccine development. Nature Reviews Immunology, 2, 251–262.CrossRefPubMedGoogle Scholar
  18. Keppler, S. J., Theil, K., Vucikuja, S., & Aichele, P. (2009). Effector T-cell differentiation during viral and bacterial infections: Role of direct IL-12 signals for cell fate decision of CD8(+) T cells. European Journal of Immunology, 39, 1774–1783.CrossRefPubMedGoogle Scholar
  19. Keppler, S. J., Rosenits, K., Koegl, T., Vucikuja, S., & Aichele, P. (2012). Signal 3 cytokines as modulators of primary immune responses during infections: The interplay of type I IFN and IL-12 in CD8 T cell responses. PLoS ONE, 7, e40865.PubMedCentralCrossRefPubMedGoogle Scholar
  20. Kolumam, G. A., Thomas, S., Thompson, L. J., Sprent, J., & Murali-Krishna, K. (2005). Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection. Journal of Experimental Medicine, 202, 637–650.PubMedCentralCrossRefPubMedGoogle Scholar
  21. Koretzky, G. A., Abtahian, F., & Silverman, M. A. (2006). SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond. Nature Reviews Immunology, 6, 67–78.CrossRefPubMedGoogle Scholar
  22. Ledbetter, J. A., Gentry, L. E., June, C. H., Rabinovitch, P. S., & Purchio, A. F. (1987). Stimulation of T cells through the CD3/T-cell receptor complex: Role of cytoplasmic calcium, protein kinase C translocation, and phosphorylation of pp60c-src in the activation pathway. Molecular and Cellular Biology, 7, 650–656.PubMedCentralPubMedGoogle Scholar
  23. Levin, A. M., Bates, D. L., Ring, A. M., Krieg, C., Lin, J. T., SU, L., Moraga, I., Raeber, M. E., Bowman, G. R., Novick, P., Pande, V. S., Fathman, C. G., Boyman, O., & Garcia, K. C. (2012). Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’. Nature, 484, 529–33.PubMedCentralCrossRefPubMedGoogle Scholar
  24. Marrack, P., Kappler, J., & Mitchell, T. (1999). Type I interferons keep activated T cells alive. Journal of Experimental Medicine, 189, 521–530.PubMedCentralCrossRefPubMedGoogle Scholar
  25. Medzhitov, R. (2001). Toll-like receptors and innate immunity. Nature Reviews Immunology, 1, 135–145.CrossRefPubMedGoogle Scholar
  26. Mehrotra, P. T., Wu, D., Crim, J. A., Mostowski, H. S., & Siegel, J. P. (1993). Effects of IL-12 on the generation of cytotoxic activity in human CD8+ T lymphocytes. Journal of Immunology, 151, 2444–2452.Google Scholar
  27. Mescher, M. F., Curtsinger, J. M., Agarwal, P., Casey, K. A., Gerner, M., Hammerbeck, C. D., Popescu, F., & Xiao, Z. (2006). Signals required for programming effector and memory development by CD8+ T cells. Immunological Reviews, 211, 81–92.CrossRefPubMedGoogle Scholar
  28. Mitchell, T. C., Hildeman, D., Kedl, R. M., Teague, T. K., Schaefer, B. C., White, J., Zhu, Y., Kappler, J., & Marrack, P. (2001). Immunological adjuvants promote activated T cell survival via induction of Bcl-3. Nature Immunology, 2, 397–402.PubMedGoogle Scholar
  29. Obar, J. J., Molloy, M. J., Jellison, E. R., Stoklasek, T. A., Zhang, W., Usherwood, E. J., & Lefrancois, L. (2010). CD4+ T cell regulation of CD25 expression controls development of short-lived effector CD8+ T cells in primary and secondary responses. Proceedings of the National Academy of Sciences of the United States of America, 107, 193–198.PubMedCentralCrossRefPubMedGoogle Scholar
  30. Pham, N. L., Badovinac, V. P., & Harty, J. T. (2009). A default pathway of memory CD8 T cell differentiation after dendritic cell immunization is deflected by encounter with inflammatory cytokines during antigen-driven proliferation. Journal of Immunology, 183, 2337–2348.CrossRefGoogle Scholar
  31. Pipkin, M. E., Sacks, J. A., Cruz-Guilloty, F., Lichtenheld, M. G., Bevan, M. J., & Rao, A. (2010). Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity, 32, 79–90.PubMedCentralCrossRefPubMedGoogle Scholar
  32. Radvanyi, L. G., Bernatchez, C., Zhang, M., Fox, P. S., Miller, P., Chacon, J., Wu, R., Lizee, G., Mahoney, S., Alvarado, G., Glass, M., Johnson, V. E., Mcmannis, J. D., Shpall, E., Prieto, V., Papadopoulos, N., Kim, K., Homsi, J., Bedikian, A., Hwu, W. J., Patel, S., Ross, M. I., Lee, J. E., Gershenwald, J. E., Lucci, A., Royal, R., Cormier, J. N., Davies, M. A., Mansaray, R., Fulbright, O. J., Toth, C., Ramachandran, R., Wardell, S., Gonzalez, A., & Hwu, P. (2012). Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clinical Cancer Research, 18, 6758–6770.PubMedCentralCrossRefPubMedGoogle Scholar
  33. Randolph, G. J., Ochando, J., & Partida-Sanchez, S. (2008). Migration of dendritic cell subsets and their precursors. Annual Review of Immunology, 26, 293–316.CrossRefPubMedGoogle Scholar
  34. Renauld, J. C., Vink, A., & Van Snick, J. (1989). Accessory signals in murine cytolytic T cell responses. Dual requirement for IL-1 and IL-6. Journal of Immunology, 143, 1894–1898.Google Scholar
  35. Restifo, N. P., Dudley, M. E., & Rosenberg, S. A. (2012). Adoptive immunotherapy for cancer: Harnessing the T cell response. Nature Reviews Immunology, 12, 269–281.CrossRefPubMedGoogle Scholar
  36. Robbins, P. F., Dudley, M. E., Wunderlich, J., El-Gamil, M., LI, Y. F., Zhou, J., Huang, J., Powell, D. J., Jr., & Rosenberg, S. A. (2004). Cutting edge: Persistence of transferred lymphocyte clonotypes correlates with cancer regression in patients receiving cell transfer therapy. Journal of Immunology, 173, 7125–7130.CrossRefGoogle Scholar
  37. Rock, K. L., & Shen, L. (2005). Cross-presentation: underlying mechanisms and role in immune surveillance. Immunological Reviews, 207, 166–183.CrossRefPubMedGoogle Scholar
  38. Rosenberg, S. A., & Dudley, M. E. (2009). Adoptive cell therapy for the treatment of patients with metastatic melanoma. Current Opinion in Immunology, 21, 233–240.PubMedCentralCrossRefPubMedGoogle Scholar
  39. Rosenberg, S. A., Yang, J. C., Sherry, R. M., Kammula, U. S., Hughes, M. S., Phan, G. Q., Citrin, D. E., Restifo, N. P., Robbins, P. F., Wunderlich, J. R., Morton, K. E., Laurencot, C. M., Steinberg, S. M., White, D. E., & Dudley, M. E. (2011). Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clinical Cancer Research, 17, 4550–4557.PubMedCentralCrossRefPubMedGoogle Scholar
  40. Saito, T., Yokosuka, T., & Hashimoto-Tane, A. (2010). Dynamic regulation of T cell activation and co-stimulation through TCR-microclusters. FEBS Letters, 584, 4865–4871.CrossRefPubMedGoogle Scholar
  41. Saveanu, L., Carroll, O., Weimershaus, M., Guermonprez, P., Firat, E., Lindo, V., Greer, F., Davoust, J., Kratzer, R., Keller, S. R., Niedermann, G., & Van Endert, P. (2009). IRAP identifies an endosomal compartment required for MHC class I cross-presentation. Science, 325, 213–217.CrossRefPubMedGoogle Scholar
  42. Schmidt, C. S., & Mescher, M. F. (1999). Adjuvant effect of IL-12: Conversion of peptide antigen administration from tolerizing to immunizing for CD8+ T cells in vivo. Journal of Immunology, 163, 2561–2567.Google Scholar
  43. Serwold, T., Gonzalez, F., Kim, J., Jacob, R., & Shastri, N. (2002). ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum. Nature, 419, 480–483.CrossRefPubMedGoogle Scholar
  44. Simon, M. M., Landolfo, S., Diamantstein, T., & Hochgeschwender, U. (1986). Antigen- and lectin-sensitized murine cytolytic T lymphocyte-precursors require both interleukin 2 and endogenously produced immune (gamma) interferon for their growth and differentiation into effector cells. Current Topics in Microbiology and Immunology, 126, 173–185.PubMedGoogle Scholar
  45. Smith-Garvin, J. E., Koretzky, G. A., & Jordan, M. S. (2009). T cell activation. Annual Review of Immunology, 27, 591–619.PubMedCentralCrossRefPubMedGoogle Scholar
  46. Sommers, C. L., Samelson, L. E., & Love, P. E. (2004). LAT: A T lymphocyte adapter protein that couples the antigen receptor to downstream signaling pathways. Bioessays, 26, 61–67.CrossRefPubMedGoogle Scholar
  47. Starbeck-Miller, G. R., Xue, H. H., & Harty, J. T. (2014). IL-12 and type I interferon prolong the division of activated CD8 T cells by maintaining high-affinity IL-2 signaling in vivo. Journal of Experimental Medicine, 211, 105–120.PubMedCentralCrossRefPubMedGoogle Scholar
  48. Trombetta, E. S., & Mellman, I. (2005). Cell biology of antigen processing in vitro and in vivo. Annual Review of Immunology, 23, 975–1028.CrossRefPubMedGoogle Scholar
  49. Valenzuela, J., Schmidt, C., & Mescher, M. (2002). The roles of IL-12 in providing a third signal for clonal expansion of naive CD8 T cells. Journal of Immunology, 169, 6842–6849.CrossRefGoogle Scholar
  50. Valenzuela, J. O., Hammerbeck, C. D., & Mescher, M. F. (2005). Cutting edge: Bcl-3 up-regulation by signal 3 cytokine (IL-12) prolongs survival of antigen-activated CD8 T cells. Journal of Immunology, 174, 600–604.CrossRefGoogle Scholar
  51. Vignali, D. A., & Kuchroo, V. K. (2012). IL-12 family cytokines: Immunological playmakers. Nature Immunology, 13, 722–728.PubMedCentralCrossRefPubMedGoogle Scholar
  52. Williams, M. A., Tyznik, A. J., & Bevan, M. J. (2006). Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature, 441, 890–893.PubMedCentralCrossRefPubMedGoogle Scholar
  53. Xue, L., Chiang, L., HE, B., Zhao, Y. Y., & Winoto, A. (2010). FoxM1, a forkhead transcription factor is a master cell cycle regulator for mouse mature T cells but not double positive thymocytes. PLoS ONE, 5, e9229.PubMedCentralCrossRefPubMedGoogle Scholar
  54. York, I. A., Chang, S. C., Saric, T., Keys, J. A., Favreau, J. M., Goldberg, A. L., & Rock, K. L. (2002). The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8–9 residues. Nature Immunology, 3, 1177–1184.CrossRefPubMedGoogle Scholar
  55. Zhang, W., Sommers, C. L., Burshtyn, D. N., Stebbins, C. C., Dejarnette, J. B., Trible, R. P., Grinberg, A., Tsay, H. C., Jacobs, H. M., Kessler, C. M., Long, E. O., Love, P. E., & Samelson, L. E. (1999). Essential role of LAT in T cell development. Immunity, 10, 323–332.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Interdisciplinary Graduate Program in ImmunologyUniversity of IowaIowa CityUSA
  2. 2.Department of MicrobiologyUniversity of IowaIowa CityUSA
  3. 3.Department of PathalogyUniversity of IowaIowa CityUSA

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