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. 1995 Sep 1;182(3):699–709. doi: 10.1084/jem.182.3.699

Control of CD4 effector fate: transforming growth factor beta 1 and interleukin 2 synergize to prevent apoptosis and promote effector expansion

PMCID: PMC2192155  PMID: 7650478

Abstract

The signals that determine the size and duration of the primary T cell immune response are not well defined. We studied CD4 T cells at an important checkpoint in their development: when they have become effectors and are ready to rapidly mediate effector functions, both via direct interaction with antigen (Ag)-presenting cells and via cytokine production. We determined the effects of specific Ag and the cytokines interleukin (IL) 2 and transforming growth factor (TGF) beta 1 on T helper cell type 2 (Th2) effector apoptosis versus expansion. Th2- polarized effector cells were generated in vitro from naive CD4 T of T cell receptor transgenic mice, and then restimulated with or without peptide Ag plus Ag-presenting cells and cytokines. In the absence of added cytokines, effector cells cultured without Ag died of apoptosis after 4-7 d. Paradoxically, Ag both induced proliferation and high levels of cytokine synthesis and accelerated effector cell death. IL-2 directly induced proliferation of effectors, supported and prolonged Ag- induced proliferation, and partially blocked apoptosis. TGF-beta did not effect proliferation or influence cytokine secretion, but it also partially blocked apoptosis. Together, IL-2 and TGF-beta synergized to almost completely block apoptosis, resulting in prolonged effector expansion and leading to the accumulation of a large pool of specific effectors. When Ag and both cytokines were present, the effector population increased 10(4)-10(5) fold over 20 d of culture. The synergy of IL-2 and TGF-beta suggests that they interfere with programmed cell death by distinct mechanisms. Since Th2 effectors are specialized to help B cells develop into antibody-secreting plasma cells, these results suggest that the availability of Ag and of the cytokines IL-2 and TGF-beta is a key factor influencing the fate of Th2 effector cells and thus the size and duration of the primary antibody response.

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Selected References

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  1. Akbar A. N., Borthwick N., Salmon M., Gombert W., Bofill M., Shamsadeen N., Pilling D., Pett S., Grundy J. E., Janossy G. The significance of low bcl-2 expression by CD45RO T cells in normal individuals and patients with acute viral infections. The role of apoptosis in T cell memory. J Exp Med. 1993 Aug 1;178(2):427–438. doi: 10.1084/jem.178.2.427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alam R., Forsythe P., Stafford S., Fukuda Y. Transforming growth factor beta abrogates the effects of hematopoietins on eosinophils and induces their apoptosis. J Exp Med. 1994 Mar 1;179(3):1041–1045. doi: 10.1084/jem.179.3.1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boehme S. A., Lenardo M. J. Propriocidal apoptosis of mature T lymphocytes occurs at S phase of the cell cycle. Eur J Immunol. 1993 Jul;23(7):1552–1560. doi: 10.1002/eji.1830230724. [DOI] [PubMed] [Google Scholar]
  4. Boise L. H., González-García M., Postema C. E., Ding L., Lindsten T., Turka L. A., Mao X., Nuñez G., Thompson C. B. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993 Aug 27;74(4):597–608. doi: 10.1016/0092-8674(93)90508-n. [DOI] [PubMed] [Google Scholar]
  5. Bradley L. M., Duncan D. D., Tonkonogy S., Swain S. L. Characterization of antigen-specific CD4+ effector T cells in vivo: immunization results in a transient population of MEL-14-, CD45RB- helper cells that secretes interleukin 2 (IL-2), IL-3, IL-4, and interferon gamma. J Exp Med. 1991 Sep 1;174(3):547–559. doi: 10.1084/jem.174.3.547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bradley L. M., Duncan D. D., Yoshimoto K., Swain S. L. Memory effectors: a potent, IL-4-secreting helper T cell population that develops in vivo after restimulation with antigen. J Immunol. 1993 Apr 15;150(8 Pt 1):3119–3130. [PubMed] [Google Scholar]
  7. Bursch W., Oberhammer F., Jirtle R. L., Askari M., Sedivy R., Grasl-Kraupp B., Purchio A. F., Schulte-Hermann R. Transforming growth factor-beta 1 as a signal for induction of cell death by apoptosis. Br J Cancer. 1993 Mar;67(3):531–536. doi: 10.1038/bjc.1993.98. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Coffman R. L., Lebman D. A., Shrader B. Transforming growth factor beta specifically enhances IgA production by lipopolysaccharide-stimulated murine B lymphocytes. J Exp Med. 1989 Sep 1;170(3):1039–1044. doi: 10.1084/jem.170.3.1039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cohen J. J. Apoptosis. Immunol Today. 1993 Mar;14(3):126–130. doi: 10.1016/0167-5699(93)90214-6. [DOI] [PubMed] [Google Scholar]
  10. Critchfield J. M., Racke M. K., Zúiga-Pflücker J. C., Cannella B., Raine C. S., Goverman J., Lenardo M. J. T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis. Science. 1994 Feb 25;263(5150):1139–1143. doi: 10.1126/science.7509084. [DOI] [PubMed] [Google Scholar]
  11. Croft M., Duncan D. D., Swain S. L. Response of naive antigen-specific CD4+ T cells in vitro: characteristics and antigen-presenting cell requirements. J Exp Med. 1992 Nov 1;176(5):1431–1437. doi: 10.1084/jem.176.5.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Croft M., Swain S. L. Analysis of CD4+ T cells that provide contact-dependent bystander help to B cells. J Immunol. 1992 Nov 15;149(10):3157–3165. [PubMed] [Google Scholar]
  13. Ewen M. E., Sluss H. K., Whitehouse L. L., Livingston D. M. TGF beta inhibition of Cdk4 synthesis is linked to cell cycle arrest. Cell. 1993 Sep 24;74(6):1009–1020. doi: 10.1016/0092-8674(93)90723-4. [DOI] [PubMed] [Google Scholar]
  14. Gillis S., Watson J. Interleukin-2 dependent culture of cytolytic T cell lines. Immunol Rev. 1981;54:81–109. doi: 10.1111/j.1600-065x.1981.tb00435.x. [DOI] [PubMed] [Google Scholar]
  15. Gorczyca W., Bigman K., Mittelman A., Ahmed T., Gong J., Melamed M. R., Darzynkiewicz Z. Induction of DNA strand breaks associated with apoptosis during treatment of leukemias. Leukemia. 1993 May;7(5):659–670. [PubMed] [Google Scholar]
  16. Green D. R., Mahboubi A., Nishioka W., Oja S., Echeverri F., Shi Y., Glynn J., Yang Y., Ashwell J., Bissonnette R. Promotion and inhibition of activation-induced apoptosis in T-cell hybridomas by oncogenes and related signals. Immunol Rev. 1994 Dec;142:321–342. doi: 10.1111/j.1600-065x.1994.tb00895.x. [DOI] [PubMed] [Google Scholar]
  17. Kabelitz D., Pohl T., Pechhold K. Activation-induced cell death (apoptosis) of mature peripheral T lymphocytes. Immunol Today. 1993 Jul;14(7):338–339. doi: 10.1016/0167-5699(93)90231-9. [DOI] [PubMed] [Google Scholar]
  18. Karasuyama H., Melchers F. Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4 or 5, using modified cDNA expression vectors. Eur J Immunol. 1988 Jan;18(1):97–104. doi: 10.1002/eji.1830180115. [DOI] [PubMed] [Google Scholar]
  19. Kehrl J. H., Wakefield L. M., Roberts A. B., Jakowlew S., Alvarez-Mon M., Derynck R., Sporn M. B., Fauci A. S. Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med. 1986 May 1;163(5):1037–1050. doi: 10.1084/jem.163.5.1037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Koff A., Ohtsuki M., Polyak K., Roberts J. M., Massagué J. Negative regulation of G1 in mammalian cells: inhibition of cyclin E-dependent kinase by TGF-beta. Science. 1993 Apr 23;260(5107):536–539. doi: 10.1126/science.8475385. [DOI] [PubMed] [Google Scholar]
  21. Kuhlman P., Moy V. T., Lollo B. A., Brian A. A. The accessory function of murine intercellular adhesion molecule-1 in T lymphocyte activation. Contributions of adhesion and co-activation. J Immunol. 1991 Mar 15;146(6):1773–1782. [PubMed] [Google Scholar]
  22. Lau L. L., Jamieson B. D., Somasundaram T., Ahmed R. Cytotoxic T-cell memory without antigen. Nature. 1994 Jun 23;369(6482):648–652. doi: 10.1038/369648a0. [DOI] [PubMed] [Google Scholar]
  23. Lee H. M., Rich S. Co-stimulation of T cell proliferation by transforming growth factor-beta 1. J Immunol. 1991 Aug 15;147(4):1127–1133. [PubMed] [Google Scholar]
  24. Lenardo M. J. Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature. 1991 Oct 31;353(6347):858–861. doi: 10.1038/353858a0. [DOI] [PubMed] [Google Scholar]
  25. Massagué J. The transforming growth factor-beta family. Annu Rev Cell Biol. 1990;6:597–641. doi: 10.1146/annurev.cb.06.110190.003121. [DOI] [PubMed] [Google Scholar]
  26. Moses H. L., Yang E. Y., Pietenpol J. A. TGF-beta stimulation and inhibition of cell proliferation: new mechanistic insights. Cell. 1990 Oct 19;63(2):245–247. doi: 10.1016/0092-8674(90)90155-8. [DOI] [PubMed] [Google Scholar]
  27. Moskophidis D., Lechner F., Pircher H., Zinkernagel R. M. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature. 1993 Apr 22;362(6422):758–761. doi: 10.1038/362758a0. [DOI] [PubMed] [Google Scholar]
  28. Nicoletti I., Migliorati G., Pagliacci M. C., Grignani F., Riccardi C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods. 1991 Jun 3;139(2):271–279. doi: 10.1016/0022-1759(91)90198-o. [DOI] [PubMed] [Google Scholar]
  29. Nossal G. J. Negative selection of lymphocytes. Cell. 1994 Jan 28;76(2):229–239. doi: 10.1016/0092-8674(94)90331-x. [DOI] [PubMed] [Google Scholar]
  30. Oltvai Z. N., Milliman C. L., Korsmeyer S. J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993 Aug 27;74(4):609–619. doi: 10.1016/0092-8674(93)90509-o. [DOI] [PubMed] [Google Scholar]
  31. Polyak K., Kato J. Y., Solomon M. J., Sherr C. J., Massague J., Roberts J. M., Koff A. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev. 1994 Jan;8(1):9–22. doi: 10.1101/gad.8.1.9. [DOI] [PubMed] [Google Scholar]
  32. Radvanyi L. G., Mills G. B., Miller R. G. Religation of the T cell receptor after primary activation of mature T cells inhibits proliferation and induces apoptotic cell death. J Immunol. 1993 Jun 15;150(12):5704–5715. [PubMed] [Google Scholar]
  33. Russell J. H., White C. L., Loh D. Y., Meleedy-Rey P. Receptor-stimulated death pathway is opened by antigen in mature T cells. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2151–2155. doi: 10.1073/pnas.88.6.2151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sorenson C. M., Barry M. A., Eastman A. Analysis of events associated with cell cycle arrest at G2 phase and cell death induced by cisplatin. J Natl Cancer Inst. 1990 May 2;82(9):749–755. doi: 10.1093/jnci/82.9.749. [DOI] [PubMed] [Google Scholar]
  35. Sprent J. T and B memory cells. Cell. 1994 Jan 28;76(2):315–322. doi: 10.1016/0092-8674(94)90338-7. [DOI] [PubMed] [Google Scholar]
  36. Swain S. L., Bradley L. M., Croft M., Tonkonogy S., Atkins G., Weinberg A. D., Duncan D. D., Hedrick S. M., Dutton R. W., Huston G. Helper T-cell subsets: phenotype, function and the role of lymphokines in regulating their development. Immunol Rev. 1991 Oct;123:115–144. doi: 10.1111/j.1600-065x.1991.tb00608.x. [DOI] [PubMed] [Google Scholar]
  37. Swain S. L. Generation and in vivo persistence of polarized Th1 and Th2 memory cells. Immunity. 1994 Oct;1(7):543–552. doi: 10.1016/1074-7613(94)90044-2. [DOI] [PubMed] [Google Scholar]
  38. Swain S. L., Huston G., Tonkonogy S., Weinberg A. Transforming growth factor-beta and IL-4 cause helper T cell precursors to develop into distinct effector helper cells that differ in lymphokine secretion pattern and cell surface phenotype. J Immunol. 1991 Nov 1;147(9):2991–3000. [PubMed] [Google Scholar]
  39. Swain S. L. Lymphokines and the immune response: the central role of interleukin-2. Curr Opin Immunol. 1991 Jun;3(3):304–310. doi: 10.1016/0952-7915(91)90028-y. [DOI] [PubMed] [Google Scholar]
  40. Swain S. L., Weinberg A. D., English M., Huston G. IL-4 directs the development of Th2-like helper effectors. J Immunol. 1990 Dec 1;145(11):3796–3806. [PubMed] [Google Scholar]
  41. Testa U., Masciulli R., Tritarelli E., Pustorino R., Mariani G., Martucci R., Barberi T., Camagna A., Valtieri M., Peschle C. Transforming growth factor-beta potentiates vitamin D3-induced terminal monocytic differentiation of human leukemic cell lines. J Immunol. 1993 Mar 15;150(6):2418–2430. [PubMed] [Google Scholar]
  42. Weinberg A. D., English M., Swain S. L. Distinct regulation of lymphokine production is found in fresh versus in vitro primed murine helper T cells. J Immunol. 1990 Mar 1;144(5):1800–1807. [PubMed] [Google Scholar]
  43. Wesselborg S., Janssen O., Kabelitz D. Induction of activation-driven death (apoptosis) in activated but not resting peripheral blood T cells. J Immunol. 1993 May 15;150(10):4338–4345. [PubMed] [Google Scholar]
  44. Zentella A., Massagué J. Transforming growth factor beta induces myoblast differentiation in the presence of mitogens. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):5176–5180. doi: 10.1073/pnas.89.11.5176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. von Boehmer H. Positive selection of lymphocytes. Cell. 1994 Jan 28;76(2):219–228. doi: 10.1016/0092-8674(94)90330-1. [DOI] [PubMed] [Google Scholar]

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