Advertisement

The IL-2 Deficiency Syndrome

A Lethal Disease Caused by Abnormal Lymphocyte Survival
  • Thomas Hünig
  • Anneliese Schimpl
Chapter
Part of the Contemporary Immunology book series (CONTIM)

Abstract

Interleukin-2 (IL-2), a cytokine with pleiotropic effects on T-, B- and NK-cells (1), binds to cell surface receptors consisting of at least three subunits (for review, see ref. 2): an IL-2 specific a-chain with low binding affinity and no signal-transducing capacity; a (3-chain that is shared with the IL-15 receptor (3,4) and participates in signaling through its cytoplasmic tail; and the “common” γ-chain (γc) shared by receptors for IL-4, -7, -9, and -15 that also takes part in signal transduction (3,5–9, for a review see ref. 10). In line with the sharing of (ß- and γ-chains by IL-2 and IL-15 receptors, a number of overlapping biological activities have been reported for both cytokines such as the induction of T- and NK-cell proliferation and, at least in humans, the promotion of B-cell growth and Ig production (4,11,12). However, additional IL-2 or IL-15-specific biological responses can so far not be excluded, and the different sources of the two lymphokines, i.e., mainly activated T-cells for IL-2 versus a wide variety of non-lymphocytic cells for IL-15 (4) predict that in vivo, the two cytokines will play quite distinct roles in the regulation of lymphocyte activation. Therefore, it will be important to keep in mind the possible contributions of IL-15 to the development and functioning of the immune system in the IL-2 deficient mice that are the object of this chapter, as compared to mice lacking components of the IL-2 receptor system.

Keywords

Deficiency Syndrome Staphylococcal Enterotoxin Lymphoid Development Bacterial Superantigens Mixed Chimera 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Smith, K. A. (1988) Interleukin-2: inception, impact and implications. Science 240, 1169 - 1176.PubMedCrossRefGoogle Scholar
  2. 2.
    Minami, Y., Kono, T., Miyazaki, T., and Taniguchi, T. (1993) The IL-2 receptor complex: its structure, function and target genes. Annu. Rev. Immunol. 11, 245 - 268.PubMedCrossRefGoogle Scholar
  3. 3.
    Giri, J. G., Ahdieh, M., Eisenman, J., Shanebeck, K., Grabstein, K., Kumaki, S., Namen, A., Park, L. S., Cosman, D., and Anderson, D. (1994) Utilization of the (3 and y chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 13, 2822 - 2830.Google Scholar
  4. 4.
    Grabstein, K. H., Eisenman, E. J., Shanebeck, K., Rauch, C., Srinivasan, S., Fung, V., Richardson, J., Schoenborn, M. A., and Ahdieh, M. (1994) Cloning of a novel T-cell growth factor that interacts with the ß chain of the interleukin 2 receptor. Science 264, 965 - 968.Google Scholar
  5. 5.
    Kondo, M., Takeshita, T., Ishii, N., Nakamura, M., Watanabe, S., Arai, K., and Sugamura, K. (1993) Sharing of the interleukin-2 (IL-2) receptor y chain between receptors for IL-2 and IL-4. Science 262, 1874 - 1877.PubMedCrossRefGoogle Scholar
  6. 6.
    Kondo, M., Takeshita, T., Higuchi, M., Nakamura, M., Sudo, T., Nishikawa, S., and Sugamura, K. (1994) Functional participation of the interleukin-2 (IL-2) receptor y chain IL-7 in receptor complexes. Science 263, 1453 - 1454.PubMedCrossRefGoogle Scholar
  7. 7.
    Russell, S. M., Keegan, A. D., Harada, N., Nakamura, Y., Noguchi, M., Leland, P., Friedmann, M. C., Miyajima, A., Puri, R. K., Paul, W. E., and Leonard, W. J. (1993) Interleukin-2 receptor y chain: a functional component of the interleukin-4 receptor. Science 262, 1880 - 1883.PubMedCrossRefGoogle Scholar
  8. 8.
    Noguchi, M., Nakamura, Y., Russell, S. M., Ziegler, S. F., Tsang, M., Cao, X., and Leonard, W. J. (1993) Interleukin-2 receptor y chain: a functional component of the interleukin-7 receptor. Science 262, 1877 - 1880.PubMedCrossRefGoogle Scholar
  9. 9.
    Russell, S. M., Johnston, J. A., Noguchi, M., Kawamura, M., Bacon, C. M., Friedmann, M., Berg, M., McVicar, D. W., Witthuhn, B. A., Silvennoinen, O., Goldman, A. S., Schmalstieg, F. C., Ihle, J. N., O’Shea, J. J., and Leonard, W. J. (1994) Interaction of IL-2Rß and yc chains with Jakl and Jak3: implications for X-SCID and X-CID. Science 266, 1042 - 1045.PubMedCrossRefGoogle Scholar
  10. 10.
    Leonard, W., Shores, E. W., and Love, P. E. (1995) Role of the common cytokine receptor y chain in cytokine signaling and lymphoid development. Immunol. Rev. 148, 97 - 114.PubMedCrossRefGoogle Scholar
  11. 11.
    Carson, W. E., and Al, E. (1994) Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J. Exp. Med. 180, 1395 - 1403.PubMedCrossRefGoogle Scholar
  12. 12.
    Armitage, R. J., Macduff, B. M., Eisenman, J., Paxton, R., and Grabstein, K. H. (1995) IL-15 has stimulatory activity for the induction of B-cell proliferation and differentiation. J. Immunol. 154, 483 - 490.PubMedGoogle Scholar
  13. 13.
    Namen, A., Lupton, S., Hjerrild, K., Wignall, J., Mochizuki, D., Schmierer, A., Mosely, B., March, C., Urdal, D., Gillis, S., and Al, E. (1988) Stimulation of B-cell progenitors by cloned murine interleukin-7. Nature 333, 571 - 573.PubMedCrossRefGoogle Scholar
  14. 14.
    Watson, J. D., Morrissey, P. J., Namen, A. E., Conlon, P. J., and Widmer, M. B. (1989) Effect of IL-7 on the growth of fetal thymocytes in culture. J. Immunol. 143, 1215 - 1222.Google Scholar
  15. 15.
    Rolink, A., Grawunder, U., Winler, T. H., Karasuyama, H, and Melchers, F. (1994) IL-2 receptor a chain expression defines a crucial stage in pre-B cell development. Int. Immunol. 6, 1257 - 1268.Google Scholar
  16. 16.
    Takacs, L., Osawa, H., and Diamantstein, T. (1984) Detection and localization by the monoclonal anti-interleukin 2 receptor antibody AMT-13 of IL-2 receptor-bearing cells in the developing thymus of the mouse embryo and in the thymus of cortisone treated mice. Eur. J. Immunol. 14, 1152 - 1156.Google Scholar
  17. 17.
    Raulet, D. H. (1985) Expression and function of interleukin-2 receptors in immature thymocytes. Nature (Lond.) 314, 101-103.Google Scholar
  18. 18.
    Ceredic, R., Lowenthal, J. W., Nabholtz, M., and MacDonald, H. R. (1985) Expression of interleukin-2 receptors as a differentiation marker on intrathymic stem cells. Nature 314, 98-100.Google Scholar
  19. Tanaka, T., Takeuchi, Y., Shiohara, T., Kitamura, F., Nakasaka, Y., Hamamura, K., Yagita, H., and Miyasaka, M. (1992) Int. Immunol. 4, 487-491.Google Scholar
  20. 20.
    Takeuchi, Y., Tanaka, T., Hamamura, K., Sugimoto, T., Miyasaka, M., Yagita, H., and Okomura, K. (1992) Expression and role of interleukin-2 receptor ß chain on CD4-8- T-cell receptor ai(3 + cells. Eur. J. Immunol. 22, 2929 - 2935.Google Scholar
  21. 21.
    Hanke, T., Mitnacht, R., Boyd, R., and Hünig, T. (1994) Induction of interleukin-2 receptor ß chain expression by self-recognition in the thymus. J. Exp. Med. 180, 1629 - 1636.Google Scholar
  22. 22.
    Cao, X., Shores, W., Hu-Li, J., Anver, M. R., Kelsall, B. L., Russell, S. M., Drago, J., Noguchi, M., Grinberg, A., Bloom, E. T., Paul, W. E., Katz, S. I., Love, P. E., and Leonard, W. J. (1995) Defective lymphoid development in mice lacking expression of the common cytokine receptor y chain. Immunity 2, 223 - 238.Google Scholar
  23. 23.
    Disanto, J. P., Müller, W., Guy-Grand, D., Fischer, A., and Rajewsky, K. (1995) Lymphoid development in mice with a targeted deletion of the interleukin-2 receptor y chain. Proc. Natl. Acad. Sci. USA 92, 377 - 381.PubMedCrossRefGoogle Scholar
  24. 24.
    Peschon, J. J., Morrissey, P. J., Grabstein, K. H., Ramsdell, F. J., Marakovsky, E., Gliniak, B. C., Park, L. S., Ziegler, S. F., Williams, D. E., Ware, C. B., Meyer, J. D., and Davison, B. L. (1994) Early lymphocyte expansion is severely impaired in interleukin-7 receptor-deficient mice. J. Exp. Med. 180, 1955-1960.Google Scholar
  25. 25.
    Schorle, H., Holtschke, T., Hünig, T., Schimpl, A., and Horak, I. (1991) Development and function of T-cells in mice rendered interleukin-2 deficient by gene targeting. Nature 352, 621-624.Google Scholar
  26. 26.
    Willerford, D. M., Chen, J., Ferry, J. A., Davidson, L., Ma, A., and Alt, F. W. (1995) Interleukin-2 receptor a chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521 - 530.Google Scholar
  27. 27.
    Suzuki, H., Kündig, T. M., Furlonger, C., Wakehan, A., Timms, E., Matsuyama, T., Schmits, R., Simard, J. J. L., Ohashi, P., Griesser, H., Taniguchi, T., Paige, C. J., and Mak, T. W. (1995) Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor B. Science 268, 1472-1476.Google Scholar
  28. 28.
    Schimpl, A., Schorle, H., Hünig, T., Berberich, I., and Horak, I. (1992) Lymphocyte subsets and immunoreactivity in IL-2 deficient mice, in New Advances on Cytokines (Romagnani, S., Mosmann, T. R., and Abbas, A. K., eds.), Raven, New York, pp. 87 - 95.Google Scholar
  29. 29.
    Schimpl, A., Hünig, T., Elbe, A., Berberich, I., Krämer, S., Merz, H., Feller, A. C., Sadlack, B., Schorle, H., and Horak, I. (1994) Development and function of the immune system in mice with targeted disruption of the interleukin 2 gene, in Transgenesis and Targeted Mutagenesis in Immunology (Bluethmann, H. and Ohashi, P., eds.), Academic, San Diego, CA, pp. 191 - 201.Google Scholar
  30. 30.
    Krämer, S., Mamalaki, C., Schimpl, A., Horak, I., Kioussis, D., and Hünig, T. (1994) Thymic selection and peripheral activation of TCR-transgenic CD8 T-cells in IL-2 deficient mice: requirement for IL-2 is restricted to the induction of cytotoxic effector function. Eur. J. Immunol. 24, 2317 - 2322.PubMedCrossRefGoogle Scholar
  31. 31.
    Nemoto, T., Takeshita, T., Ishii, N., Kondo, M., Higuchi, M., Satomi, S., Nakamura, M., Mori, S., and Sugamura, K. (1995) Differences in the interleukin-2 (IL-2) receptor system in human and mouse: a chain is required for formation of the functional mouse IL-2 receptor. Eur. J. Immunol. 25, 3001 - 3005.PubMedCrossRefGoogle Scholar
  32. 32.
    Schimpl, A., Hünig, T., Berberich, I., Erb, K., Elbe, A., Stingl, G., Sadlack, B., Schorle, H., and Horak, I. (1992) Lymphocyte development and immunoreactivity in IL-2 deficient mice, in Progress in Immunology VIII ( Gergely, Y. et al., eds.), Springer-Verlag, Budapest, pp. 305 - 311.Google Scholar
  33. 33.
    Kündig, T. M., Schorle, H., Bachmann, M. F., Hengartner, H., Zinkernagel, R. M., and Horak, I. (1993) Immune responses in interleukin-2 deficient mice. Science 262,1059-1061.Google Scholar
  34. 34.
    Kneitz, B., Herrmann, T., Yonehara, S., and Schimpl, A. (1995) Normal clonal expansion but impaired Fas-mediated cell death and anergy induction in IL-2 deficient mice. Eur. J. Immunol. 25, 2572 - 2577.PubMedCrossRefGoogle Scholar
  35. 35.
    Sadlack, B., Merz, H., Schorle, H., Schimpl, A., Feller, A. C., and Horak, I. (1993) Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253 - 261.Google Scholar
  36. 36.
    Horak, I., Löhler, J., Ma, A., and Smith, K. A. (1995) Interleukin-2 deficient mice: A new model to study autoimmunity and self-tolerance. Immunol. Rev. 148, 35-44.Google Scholar
  37. 37.
    Sadlack, B., Löhler, J., Schorle, H., Klebb, G., Haber, H., Sickel, E., Noelle, R. J., and Horak, I. (1995) Generalized autoimmune disease in interleukin-2 deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur. J. Immunol. 25, 3053 - 3059.PubMedCrossRefGoogle Scholar
  38. 38.
    Sadlack, B., Kühn, R., Schorle, H., Rajewsky, K., Müller, W., and Horak, I. (1994) Development and function of lymphocytes in mice deficient for both interleukins 2 and 4. Eur. J. Immunol. 24, 281 - 284.PubMedCrossRefGoogle Scholar
  39. Kühn,R., Lühler, J., Rennick, D., Rajewsky, K., and Müller, W. (1993) Interleukin-l0-deficient mice develop chronic enterocolitis Cell 75, 263-274 Google Scholar
  40. 40.
    Mombaerts, A., Mizoguchi, E., Grusby, M. J., Glimcher, L. H., Bhan, A. K., and Tonegawa, S. (1993) Spontaneous development of inflammatory bowel disease in T-cell receptor mutant mice. Cell 75, 275 - 282.CrossRefGoogle Scholar
  41. 41.
    Ma, A., Datta, M., Margosian, E., and Horak, I. (1995) T cells, but not B cells, are required for bowel inflammation in IL-2 deficient mice. J. Exp. Med. 182, 1567-1572.Google Scholar
  42. 42.
    Krümer, S., Schimpl, A., and Hünig, T. (1995) Immunopathology of Interleukin (IL) 2-deficient mice: thymus dependence and suppression by thymus-dependent cells with an intact IL-2 gene. J. Exp. Med. 182, 1769-1776.Google Scholar
  43. 43.
    Swain, S. L., Bradley, L. M., Croft, M., Tonkonogi, S., Atkins, G., Weinberg, A. D., Duncan, D. D., Hedrick, S. M., Dutton., R. W., and Huston, G. (1991) Helper T cell subsets: phenotype, function and the role of lymphokines in regulating their development. Immunol. Rev. 123, 115 - 144.Google Scholar
  44. 44.
    Steiger, J., Nickerson, P. W., Steurer, W., Moscovitch-Lopatin, M., and Strom, T. B. (1995) IL-2 knockout recipient mice reject islet cell allografts. J. Immunol. 155, 489 - 498.PubMedGoogle Scholar
  45. 45.
    Hellmann, T., and MacDonald, H. R. (1993) The CD8+ T cell response to staphylococcal enterotoxins. Sem. Immunol. 5, 33 - 39.CrossRefGoogle Scholar
  46. 46.
    Huang, L., Soldevila, G., Leeker, M., Flavell, R., and Crispe, I. N. (1994) The liver eliminates T cells undergoing antigen-triggered apoptosis in vivo. Immunity 1, 741 - 749.PubMedCrossRefGoogle Scholar
  47. 47.
    Schimpl, A. and Wittig, T. (1994) Interleukin-2 overexpression and deprivation: consequences for lymphopoiesis and T cell function, in Overexpression and Knockout of Cytokines in Transgenic Mice ( Yacob, C. O., ed.), Academic, London, pp. 31 - 45.Google Scholar
  48. 48.
    MacDonald, H. R., Lees, R. K., Baschieri, S., Hellmann, T., Lussow, A. R. (1993) Peripheral T-cell reactivity to bacterial superantigens in vivo: the response/anergy paradox. Immunol. Rev. 133, 105 - 117.PubMedCrossRefGoogle Scholar
  49. 49.
    Heeg, K., Bendix, S., Miethke, T., and Wagner, H. (1993) Induction of unresponsiveness to the superantigen staphylococcal enterotoxin B: cyclosporin A resistant split unresponsiveness unfolds in vivo without preceding clonal expansion. Int. Immunol. 5, 929 - 937.PubMedCrossRefGoogle Scholar
  50. 50.
    Krammer, P. H., Behrmann, I., Daniel, P., Dhein, J., and Debatin, K. M. (1994) Regulation of apoptosis in the immune system. Curr. Opin. Immunol. 6, 279 - 289.PubMedCrossRefGoogle Scholar
  51. 51.
    Singer, G. C., Carrera, A. C., Marshak-Rothstein, A., Martinez-A, C., and Abbas, A. K. (1994) Apoptosis, Fas and systemic aoutimmunity: the MRLlpr/lpr model. Curr. Opin. Immunol. 6, 913 - 920.CrossRefGoogle Scholar
  52. 52.
    White, E. (1996) Life, death and the persuit of apoptosis. Genes Dev. 10, 1 - 15.PubMedCrossRefGoogle Scholar
  53. 53.
    Jiang, H., Ware, R., Stall, A., Flaherty, L., Chess, L., and Pernis, B. (1995) Murine CD8+ T cells that specifically delete autologous CD4+ T cells expressing Vß8 TCR: a role of the Qa-1 molecule. Immunity 2, 185 - 194.PubMedCrossRefGoogle Scholar
  54. 54.
    Razi-Wolf, Z., Hollander, G. A., and Reiser, H. (1996) Activation of CD4+ T lymphocytes from interleukin 2-deficient mice by costimulatory B7 molecules. Proc. Natl. Acad. Sci. USA 93, 2903 - 2908.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Thomas Hünig
  • Anneliese Schimpl

There are no affiliations available

Personalised recommendations