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. 1993 Feb 1;177(2):305–316. doi: 10.1084/jem.177.2.305

Cutaneous lymphoproliferation and lymphomas in interleukin 7 transgenic mice

PMCID: PMC2190896  PMID: 7678850

Abstract

To investigate the role of interleukin 7 (IL-7) in the development of the lymphoid system, we have generated two lines of transgenic mice carrying an IL-7 cDNA fused to an immunoglobulin heavy chain promoter and enhancer. This transgene is expressed in the bone marrow, lymph nodes, spleen, thymus, and skin provoking a perturbation of T cell development characterized by a marked reduction of CD4+ CD8+ (double- positive) thymocytes. Quite unexpectedly, however, both lines also develop a progressive cutaneous disorder involving a dermal lymphoid infiltrate that results in progressive alopecia, hyperkeratosis, and exfoliation. Although the infiltrate is primarily composed of T lineage cells, its development is not impeded in the athymic nu/nu background. Furthermore, the phenotype can be transmitted horizontally by transplanting lymphoid tissues or skin to syngeneic wild-type mice. Thus, the phenotype is conveyed by skin-homing, mobile cells (presumably the infiltrating lymphocytes) in a cell-autonomous fashion. In addition to the skin phenotype, this transgene also provokes the development of a lymphoproliferative disorder that induces B and T cell lymphomas within the first 4 mo of life. These findings suggest potential physiologic actions of IL-7 in T cell development and in cutaneous immunity. They also demonstrate that IL-7 can act as an oncogene in the living organism.

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Selected References

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  1. Beller D. I., Springer T. A., Schreiber R. D. Anti-Mac-1 selectively inhibits the mouse and human type three complement receptor. J Exp Med. 1982 Oct 1;156(4):1000–1009. doi: 10.1084/jem.156.4.1000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brooks E. G., Wirt D. P., Goldblum R. M., Vaidya S., Asuncion M. T., Patterson J. C., Ware C. F., Klimpel G. R. Double-negative (CD4- CD8-) T cells with an alpha/beta T cell receptor. Non-MHC-restricted cytolytic activity and lymphokine production. J Immunol. 1990 Jun 15;144(12):4507–4512. [PubMed] [Google Scholar]
  3. Budd R. C., Miescher G. C., Howe R. C., Lees R. K., Bron C., MacDonald H. R. Developmentally regulated expression of T cell receptor beta chain variable domains in immature thymocytes. J Exp Med. 1987 Aug 1;166(2):577–582. doi: 10.1084/jem.166.2.577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chazen G. D., Pereira G. M., LeGros G., Gillis S., Shevach E. M. Interleukin 7 is a T-cell growth factor. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5923–5927. doi: 10.1073/pnas.86.15.5923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Coffman R. L. Surface antigen expression and immunoglobulin gene rearrangement during mouse pre-B cell development. Immunol Rev. 1982;69:5–23. doi: 10.1111/j.1600-065x.1983.tb00446.x. [DOI] [PubMed] [Google Scholar]
  6. Conlon P. J., Morrissey P. J., Nordan R. P., Grabstein K. H., Prickett K. S., Reed S. G., Goodwin R., Cosman D., Namen A. E. Murine thymocytes proliferate in direct response to interleukin-7. Blood. 1989 Sep;74(4):1368–1373. [PubMed] [Google Scholar]
  7. Crispe I. N., Moore M. W., Husmann L. A., Smith L., Bevan M. J., Shimonkevitz R. P. Differentiation potential of subsets of CD4-8- thymocytes. Nature. 1987 Sep 24;329(6137):336–339. doi: 10.1038/329336a0. [DOI] [PubMed] [Google Scholar]
  8. Damia G., Komschlies K. L., Faltynek C. R., Ruscetti F. W., Wiltrout R. H. Administration of recombinant human interleukin-7 alters the frequency and number of myeloid progenitor cells in the bone marrow and spleen of mice. Blood. 1992 Mar 1;79(5):1121–1129. [PubMed] [Google Scholar]
  9. Davis T. H., Morton C. C., Miller-Cassman R., Balk S. P., Kadin M. E. Hodgkin's disease, lymphomatoid papulosis, and cutaneous T-cell lymphoma derived from a common T-cell clone. N Engl J Med. 1992 Apr 23;326(17):1115–1122. doi: 10.1056/NEJM199204233261704. [DOI] [PubMed] [Google Scholar]
  10. Early P., Rogers J., Davis M., Calame K., Bond M., Wall R., Hood L. Two mRNAs can be produced from a single immunoglobulin mu gene by alternative RNA processing pathways. Cell. 1980 Jun;20(2):313–319. doi: 10.1016/0092-8674(80)90617-0. [DOI] [PubMed] [Google Scholar]
  11. Everson M. P., Eldridge J. H., Koopman W. J. Synergism of interleukin 7 with the thymocyte growth factors interleukin 2, interleukin 6, and tumor necrosis factor alpha in the induction of thymocyte proliferation. Cell Immunol. 1990 May;127(2):470–482. doi: 10.1016/0008-8749(90)90147-j. [DOI] [PubMed] [Google Scholar]
  12. Fenton R. G., Marrack P., Kappler J. W., Kanagawa O., Seidman J. G. Isotypic exclusion of gamma delta T cell receptors in transgenic mice bearing a rearranged beta-chain gene. Science. 1988 Aug 26;241(4869):1089–1092. doi: 10.1126/science.2970670. [DOI] [PubMed] [Google Scholar]
  13. Fowlkes B. J., Kruisbeek A. M., Ton-That H., Weston M. A., Coligan J. E., Schwartz R. H., Pardoll D. M. A novel population of T-cell receptor alpha beta-bearing thymocytes which predominantly expresses a single V beta gene family. Nature. 1987 Sep 17;329(6136):251–254. doi: 10.1038/329251a0. [DOI] [PubMed] [Google Scholar]
  14. Fowlkes B. J., Pardoll D. M. Molecular and cellular events of T cell development. Adv Immunol. 1989;44:207–264. doi: 10.1016/s0065-2776(08)60643-4. [DOI] [PubMed] [Google Scholar]
  15. Groh V., Fabbi M., Hochstenbach F., Maziarz R. T., Strominger J. L. Double-negative (CD4-CD8-) lymphocytes bearing T-cell receptor alpha and beta chains in normal human skin. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5059–5063. doi: 10.1073/pnas.86.13.5059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Grosschedl R., Weaver D., Baltimore D., Costantini F. Introduction of a mu immunoglobulin gene into the mouse germ line: specific expression in lymphoid cells and synthesis of functional antibody. Cell. 1984 Oct;38(3):647–658. doi: 10.1016/0092-8674(84)90259-9. [DOI] [PubMed] [Google Scholar]
  17. Guidos C. J., Weissman I. L., Adkins B. Developmental potential of CD4-8- thymocytes. Peripheral progeny include mature CD4-8- T cells bearing alpha beta T cell receptor. J Immunol. 1989 Jun 1;142(11):3773–3780. [PubMed] [Google Scholar]
  18. Ishida Y., Nishi M., Taguchi O., Inaba K., Minato N., Kawaichi M., Honjo T. Effects of the deregulated expression of human interleukin-2 in transgenic mice. Int Immunol. 1989;1(2):113–120. doi: 10.1093/intimm/1.2.113. [DOI] [PubMed] [Google Scholar]
  19. Kennedy J. D., Pierce C. W., Lake J. P. Extrathymic T cell maturation. Phenotypic analysis of T cell subsets in nude mice as a function of age. J Immunol. 1992 Mar 15;148(6):1620–1629. [PubMed] [Google Scholar]
  20. Kubo R. T., Born W., Kappler J. W., Marrack P., Pigeon M. Characterization of a monoclonal antibody which detects all murine alpha beta T cell receptors. J Immunol. 1989 Apr 15;142(8):2736–2742. [PubMed] [Google Scholar]
  21. Kuzel T. M., Roenigk H. H., Jr, Rosen S. T. Mycosis fungoides and the Sézary syndrome: a review of pathogenesis, diagnosis, and therapy. J Clin Oncol. 1991 Jul;9(7):1298–1313. doi: 10.1200/JCO.1991.9.7.1298. [DOI] [PubMed] [Google Scholar]
  22. Lasky L. A. Lectin cell adhesion molecules (LEC-CAMs): a new family of cell adhesion proteins involved with inflammation. J Cell Biochem. 1991 Feb;45(2):139–146. doi: 10.1002/jcb.240450204. [DOI] [PubMed] [Google Scholar]
  23. Ledbetter J. A., Herzenberg L. A. Xenogeneic monoclonal antibodies to mouse lymphoid differentiation antigens. Immunol Rev. 1979;47:63–90. doi: 10.1111/j.1600-065x.1979.tb00289.x. [DOI] [PubMed] [Google Scholar]
  24. Lee G., Namen A. E., Gillis S., Kincade P. W. Recombinant interleukin-7 supports the growth of normal B lymphocyte precursors. Curr Top Microbiol Immunol. 1988;141:16–18. doi: 10.1007/978-3-642-74006-0_3. [DOI] [PubMed] [Google Scholar]
  25. Lynch D. H., Namen A. E., Miller R. E. In vivo evaluation of the effects of interleukins 2, 4 and 7 on enhancing the immunotherapeutic efficacy of anti-tumor cytotoxic T lymphocytes. Eur J Immunol. 1991 Dec;21(12):2977–2985. doi: 10.1002/eji.1830211212. [DOI] [PubMed] [Google Scholar]
  26. McKay I. A., Leigh I. M. Epidermal cytokines and their roles in cutaneous wound healing. Br J Dermatol. 1991 Jun;124(6):513–518. doi: 10.1111/j.1365-2133.1991.tb04942.x. [DOI] [PubMed] [Google Scholar]
  27. Mieno M., Suto R., Obata Y., Udono H., Takahashi T., Shiku H., Nakayama E. CD4-CD8- T cell receptor alpha beta T cells: generation of an in vitro major histocompatibility complex class I specific cytotoxic T lymphocyte response and allogeneic tumor rejection. J Exp Med. 1991 Jul 1;174(1):193–201. doi: 10.1084/jem.174.1.193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Morello D., Lavenu A., Bandeira A., Portnoi D., Gaillard J., Babinet C. Lymphoproliferative syndrome associated with c-myc expression driven by a class I gene promoter in transgenic mice. Oncogene Res. 1989;4(2):111–125. [PubMed] [Google Scholar]
  29. Morrissey P. J., Conlon P., Charrier K., Braddy S., Alpert A., Williams D., Namen A. E., Mochizuki D. Administration of IL-7 to normal mice stimulates B-lymphopoiesis and peripheral lymphadenopathy. J Immunol. 1991 Jul 15;147(2):561–568. [PubMed] [Google Scholar]
  30. Morrissey P. J., Goodwin R. G., Nordan R. P., Anderson D., Grabstein K. H., Cosman D., Sims J., Lupton S., Acres B., Reed S. G. Recombinant interleukin 7, pre-B cell growth factor, has costimulatory activity on purified mature T cells. J Exp Med. 1989 Mar 1;169(3):707–716. doi: 10.1084/jem.169.3.707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Murray R., Suda T., Wrighton N., Lee F., Zlotnik A. IL-7 is a growth and maintenance factor for mature and immature thymocyte subsets. Int Immunol. 1989;1(5):526–531. doi: 10.1093/intimm/1.5.526. [DOI] [PubMed] [Google Scholar]
  32. Namen A. E., Lupton S., Hjerrild K., Wignall J., Mochizuki D. Y., Schmierer A., Mosley B., March C. J., Urdal D., Gillis S. Stimulation of B-cell progenitors by cloned murine interleukin-7. Nature. 1988 Jun 9;333(6173):571–573. doi: 10.1038/333571a0. [DOI] [PubMed] [Google Scholar]
  33. Namen A. E., Schmierer A. E., March C. J., Overell R. W., Park L. S., Urdal D. L., Mochizuki D. Y. B cell precursor growth-promoting activity. Purification and characterization of a growth factor active on lymphocyte precursors. J Exp Med. 1988 Mar 1;167(3):988–1002. doi: 10.1084/jem.167.3.988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Okazaki H., Ito M., Sudo T., Hattori M., Kano S., Katsura Y., Minato N. IL-7 promotes thymocyte proliferation and maintains immunocompetent thymocytes bearing alpha beta or gamma delta T-cell receptors in vitro: synergism with IL-2. J Immunol. 1989 Nov 1;143(9):2917–2922. [PubMed] [Google Scholar]
  35. Samaridis J., Casorati G., Traunecker A., Iglesias A., Gutierrez J. C., Müller U., Palacios R. Development of lymphocytes in interleukin 7-transgenic mice. Eur J Immunol. 1991 Feb;21(2):453–460. doi: 10.1002/eji.1830210230. [DOI] [PubMed] [Google Scholar]
  36. Scollay R., Wilson A., D'Amico A., Kelly K., Egerton M., Pearse M., Wu L., Shortman K. Developmental status and reconstitution potential of subpopulations of murine thymocytes. Immunol Rev. 1988 Aug;104:81–120. doi: 10.1111/j.1600-065x.1988.tb00760.x. [DOI] [PubMed] [Google Scholar]
  37. Shipp M. A., Vijayaraghavan J., Schmidt E. V., Masteller E. L., D'Adamio L., Hersh L. B., Reinherz E. L. Common acute lymphoblastic leukemia antigen (CALLA) is active neutral endopeptidase 24.11 ("enkephalinase"): direct evidence by cDNA transfection analysis. Proc Natl Acad Sci U S A. 1989 Jan;86(1):297–301. doi: 10.1073/pnas.86.1.297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Slater D. N. Cutaneous lymphoproliferative disorders: an assessment of recent investigative techniques. Br J Dermatol. 1991 Apr;124(4):309–323. doi: 10.1111/j.1365-2133.1991.tb00590.x. [DOI] [PubMed] [Google Scholar]
  39. Stingl G., Tschachler E., Groh V., Wolff K., Hauser C. The immune functions of epidermal cells. Immunol Ser. 1989;46:3–72. [PubMed] [Google Scholar]
  40. Stoolman L. M. Adhesion molecules controlling lymphocyte migration. Cell. 1989 Mar 24;56(6):907–910. doi: 10.1016/0092-8674(89)90620-x. [DOI] [PubMed] [Google Scholar]
  41. Suda T., Murray R., Guidos C., Zlotnik A. Growth-promoting activity of IL-1 alpha, IL-6, and tumor necrosis factor-alpha in combination with IL-2, IL-4, or IL-7 on murine thymocytes. Differential effects on CD4/CD8 subsets and on CD3+/CD3- double-negative thymocytes. J Immunol. 1990 Apr 15;144(8):3039–3045. [PubMed] [Google Scholar]
  42. Suda T., Okada S., Suda J., Miura Y., Ito M., Sudo T., Hayashi S., Nishikawa S., Nakauchi H. A stimulatory effect of recombinant murine interleukin-7 (IL-7) on B-cell colony formation and an inhibitory effect of IL-1 alpha. Blood. 1989 Nov 1;74(6):1936–1941. [PubMed] [Google Scholar]
  43. Sullivan S., Bergstresser P. R., Tigelaar R. E., Streilein J. W. FACS purification of bone marrow-derived epidermal populations in mice: Langerhans cells and Thy-1+ dendritic cells. J Invest Dermatol. 1985 Jun;84(6):491–495. doi: 10.1111/1523-1747.ep12273454. [DOI] [PubMed] [Google Scholar]
  44. Tepper R. I., Levinson D. A., Stanger B. Z., Campos-Torres J., Abbas A. K., Leder P. IL-4 induces allergic-like inflammatory disease and alters T cell development in transgenic mice. Cell. 1990 Aug 10;62(3):457–467. doi: 10.1016/0092-8674(90)90011-3. [DOI] [PubMed] [Google Scholar]
  45. Watson J. D., Morrissey P. J., Namen A. E., Conlon P. J., Widmer M. B. Effect of IL-7 on the growth of fetal thymocytes in culture. J Immunol. 1989 Aug 15;143(4):1215–1222. [PubMed] [Google Scholar]
  46. Weiss L. M., Wood G. S., Hu E., Abel E. A., Hoppe R. T., Sklar J. Detection of clonal T-cell receptor gene rearrangements in the peripheral blood of patients with mycosis fungoides/Sezary syndrome. J Invest Dermatol. 1989 Apr;92(4):601–604. doi: 10.1111/1523-1747.ep12712131. [DOI] [PubMed] [Google Scholar]
  47. Whitlock C. A., Robertson D., Witte O. N. Murine B cell lymphopoiesis in long term culture. J Immunol Methods. 1984 Mar 16;67(2):353–369. doi: 10.1016/0022-1759(84)90475-7. [DOI] [PubMed] [Google Scholar]
  48. Widmer M. B., Morrissey P. J., Namen A. E., Voice R. F., Watson J. D. Interleukin 7 stimulates growth of fetal thymic precursors of cytolytic cells: induction of effector function by interleukin 2 and inhibition by interleukin 4. Int Immunol. 1990;2(11):1055–1061. doi: 10.1093/intimm/2.11.1055. [DOI] [PubMed] [Google Scholar]
  49. Williams I. R., Unanue E. R. Costimulatory requirements of murine Th1 clones. The role of accessory cell-derived signals in responses to anti-CD3 antibody. J Immunol. 1990 Jul 1;145(1):85–93. [PubMed] [Google Scholar]
  50. Wirt D. P., Brooks E. G., Vaidya S., Klimpel G. R., Waldmann T. A., Goldblum R. M. Novel T-lymphocyte population in combined immunodeficiency with features of graft-versus-host disease. N Engl J Med. 1989 Aug 10;321(6):370–374. doi: 10.1056/NEJM198908103210606. [DOI] [PubMed] [Google Scholar]
  51. Young J. C., Gishizky M. L., Witte O. N. Hyperexpression of interleukin-7 is not necessary or sufficient for transformation of a pre-B lymphoid cell line. Mol Cell Biol. 1991 Feb;11(2):854–863. doi: 10.1128/mcb.11.2.854. [DOI] [PMC free article] [PubMed] [Google Scholar]

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