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. 1993 Nov 1;178(5):1645–1653. doi: 10.1084/jem.178.5.1645

CD28-induced costimulation of T helper type 2 cells mediated by induction of responsiveness to interleukin 4

PMCID: PMC2191256  PMID: 8228811

Abstract

Type 1 and type 2 cloned T helper (Th) cells are believed to require different antigen-presenting cell (APC)-derived costimuli for proliferation. In the case of Th1-cloned T cells, CD28 signaling costimulates production of autocrine interleukin 2 (IL-2). Th2 cells produce their autocrine growth factor, IL-4, without costimulation, but require APC-derived costimuli, or IL-1, to respond to IL-4. Here we demonstrate that engagement of CD28 on Th2 cells with anti-CD28 antibody or with APC-associated B7 costimulates Th2 responsiveness to IL-4 but does not affect IL-4 or IL-2 production by Th2 cells. Costimulation of Th2 cells via CD28 appears to involve the induction of IL-1 production by Th2 cells, which acts in an autocrine fashion to induce IL-4 responsiveness. These results suggest that CD28-induced costimulation plays an important role in responses mediated by both types of Th cells.

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Selected References

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  1. Aruffo A., Seed B. Molecular cloning of a CD28 cDNA by a high-efficiency COS cell expression system. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8573–8577. doi: 10.1073/pnas.84.23.8573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bhardwaj N., Lau L. L., Friedman S. M., Crow M. K., Steinman R. M. Interleukin 1 production during accessory cell-dependent mitogenesis of T lymphocytes. J Exp Med. 1989 Mar 1;169(3):1121–1136. doi: 10.1084/jem.169.3.1121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Caput D., Beutler B., Hartog K., Thayer R., Brown-Shimer S., Cerami A. Identification of a common nucleotide sequence in the 3'-untranslated region of mRNA molecules specifying inflammatory mediators. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1670–1674. doi: 10.1073/pnas.83.6.1670. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chiodetti L., Schwartz R. H. Induction of competence to respond to IL-4 by CD4+ T helper type 1 cells requires costimulation. J Immunol. 1992 Aug 1;149(3):901–910. [PubMed] [Google Scholar]
  5. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  6. Damle N. K., Hansen J. A., Good R. A., Gupta S. Monoclonal antibody analysis of human T lymphocyte subpopulations exhibiting autologous mixed lymphocyte reaction. Proc Natl Acad Sci U S A. 1981 Aug;78(8):5096–5098. doi: 10.1073/pnas.78.8.5096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Durum S. K., Schmidt J. A., Oppenheim J. J. Interleukin 1: an immunological perspective. Annu Rev Immunol. 1985;3:263–287. doi: 10.1146/annurev.iy.03.040185.001403. [DOI] [PubMed] [Google Scholar]
  8. Evavold B. D., Quintans J. Accessory cell function of Th2 clones. J Immunol. 1989 Sep 15;143(6):1784–1789. [PubMed] [Google Scholar]
  9. Evavold B. D., Yokoyama A., Hirsch R., Bluestone J. A., Quintans J. T helper 2 (Th2) but not Th1 clones co-stimulate resting T cells in the presence of anti-CD3 monoclonal antibody. Int Immunol. 1989;1(4):443–449. doi: 10.1093/intimm/1.4.443. [DOI] [PubMed] [Google Scholar]
  10. Fraser J. D., Irving B. A., Crabtree G. R., Weiss A. Regulation of interleukin-2 gene enhancer activity by the T cell accessory molecule CD28. Science. 1991 Jan 18;251(4991):313–316. doi: 10.1126/science.1846244. [DOI] [PubMed] [Google Scholar]
  11. Freeman G. J., Freedman A. S., Segil J. M., Lee G., Whitman J. F., Nadler L. M. B7, a new member of the Ig superfamily with unique expression on activated and neoplastic B cells. J Immunol. 1989 Oct 15;143(8):2714–2722. [PubMed] [Google Scholar]
  12. Gimmi C. D., Freeman G. J., Gribben J. G., Sugita K., Freedman A. S., Morimoto C., Nadler L. M. B-cell surface antigen B7 provides a costimulatory signal that induces T cells to proliferate and secrete interleukin 2. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6575–6579. doi: 10.1073/pnas.88.15.6575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Goldman J. P., Spencer D. M., Raulet D. H. Ordered rearrangement of variable region genes of the T cell receptor gamma locus correlates with transcription of the unrearranged genes. J Exp Med. 1993 Mar 1;177(3):729–739. doi: 10.1084/jem.177.3.729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Greenbaum L. A., Horowitz J. B., Woods A., Pasqualini T., Reich E. P., Bottomly K. Autocrine growth of CD4+ T cells. Differential effects of IL-1 on helper and inflammatory T cells. J Immunol. 1988 Mar 1;140(5):1555–1560. [PubMed] [Google Scholar]
  15. Gross J. A., St John T., Allison J. P. The murine homologue of the T lymphocyte antigen CD28. Molecular cloning and cell surface expression. J Immunol. 1990 Apr 15;144(8):3201–3210. [PubMed] [Google Scholar]
  16. Hannum C. H., Wilcox C. J., Arend W. P., Joslin F. G., Dripps D. J., Heimdal P. L., Armes L. G., Sommer A., Eisenberg S. P., Thompson R. C. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. 1990 Jan 25;343(6256):336–340. doi: 10.1038/343336a0. [DOI] [PubMed] [Google Scholar]
  17. Harding F. A., McArthur J. G., Gross J. A., Raulet D. H., Allison J. P. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature. 1992 Apr 16;356(6370):607–609. doi: 10.1038/356607a0. [DOI] [PubMed] [Google Scholar]
  18. Holsti M. A., Raulet D. H. IL-6 and IL-1 synergize to stimulate IL-2 production and proliferation of peripheral T cells. J Immunol. 1989 Oct 15;143(8):2514–2519. [PubMed] [Google Scholar]
  19. Jenkins M. K., Pardoll D. M., Mizuguchi J., Quill H., Schwartz R. H. T-cell unresponsiveness in vivo and in vitro: fine specificity of induction and molecular characterization of the unresponsive state. Immunol Rev. 1987 Feb;95:113–135. doi: 10.1111/j.1600-065x.1987.tb00502.x. [DOI] [PubMed] [Google Scholar]
  20. Kaye J., Gillis S., Mizel S. B., Shevach E. M., Malek T. R., Dinarello C. A., Lachman L. B., Janeway C. A., Jr Growth of a cloned helper T cell line induced by a monoclonal antibody specific for the antigen receptor: interleukin 1 is required for the expression of receptors for interleukin 2. J Immunol. 1984 Sep;133(3):1339–1345. [PubMed] [Google Scholar]
  21. Kaye J., Porcelli S., Tite J., Jones B., Janeway C. A., Jr Both a monoclonal antibody and antisera specific for determinants unique to individual cloned helper T cell lines can substitute for antigen and antigen-presenting cells in the activation of T cells. J Exp Med. 1983 Sep 1;158(3):836–856. doi: 10.1084/jem.158.3.836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Killar L., MacDonald G., West J., Woods A., Bottomly K. Cloned, Ia-restricted T cells that do not produce interleukin 4(IL 4)/B cell stimulatory factor 1(BSF-1) fail to help antigen-specific B cells. J Immunol. 1987 Mar 15;138(6):1674–1679. [PubMed] [Google Scholar]
  23. Kim J., Woods A., Becker-Dunn E., Bottomly K. Distinct functional phenotypes of cloned Ia-restricted helper T cells. J Exp Med. 1985 Jul 1;162(1):188–201. doi: 10.1084/jem.162.1.188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Koide S., Steinman R. M. Induction of murine interleukin 1: stimuli and responsive primary cells. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3802–3806. doi: 10.1073/pnas.84.11.3802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. Lichtman A. H., Chin J., Schmidt J. A., Abbas A. K. Role of interleukin 1 in the activation of T lymphocytes. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9699–9703. doi: 10.1073/pnas.85.24.9699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lichtman A. H., Kurt-Jones E. A., Abbas A. K. B-cell stimulatory factor 1 and not interleukin 2 is the autocrine growth factor for some helper T lymphocytes. Proc Natl Acad Sci U S A. 1987 Feb;84(3):824–827. doi: 10.1073/pnas.84.3.824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lindstein T., June C. H., Ledbetter J. A., Stella G., Thompson C. B. Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway. Science. 1989 Apr 21;244(4902):339–343. doi: 10.1126/science.2540528. [DOI] [PubMed] [Google Scholar]
  29. Linsley P. S., Brady W., Grosmaire L., Aruffo A., Damle N. K., Ledbetter J. A. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med. 1991 Mar 1;173(3):721–730. doi: 10.1084/jem.173.3.721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Mosmann T. R., Bond M. W., Coffman R. L., Ohara J., Paul W. E. T-cell and mast cell lines respond to B-cell stimulatory factor 1. Proc Natl Acad Sci U S A. 1986 Aug;83(15):5654–5658. doi: 10.1073/pnas.83.15.5654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
  32. Mueller D. L., Jenkins M. K., Schwartz R. H. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445–480. doi: 10.1146/annurev.iy.07.040189.002305. [DOI] [PubMed] [Google Scholar]
  33. Ohara J., Paul W. E. Production of a monoclonal antibody to and molecular characterization of B-cell stimulatory factor-1. Nature. 1985 May 23;315(6017):333–336. doi: 10.1038/315333a0. [DOI] [PubMed] [Google Scholar]
  34. Ozato K., Mayer N., Sachs D. H. Hybridoma cell lines secreting monoclonal antibodies to mouse H-2 and Ia antigens. J Immunol. 1980 Feb;124(2):533–540. [PubMed] [Google Scholar]
  35. Quill H., Schwartz R. H. Stimulation of normal inducer T cell clones with antigen presented by purified Ia molecules in planar lipid membranes: specific induction of a long-lived state of proliferative nonresponsiveness. J Immunol. 1987 Jun 1;138(11):3704–3712. [PubMed] [Google Scholar]
  36. Schwartz R. H. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell. 1992 Dec 24;71(7):1065–1068. doi: 10.1016/s0092-8674(05)80055-8. [DOI] [PubMed] [Google Scholar]
  37. Shaw G., Kamen R. A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell. 1986 Aug 29;46(5):659–667. doi: 10.1016/0092-8674(86)90341-7. [DOI] [PubMed] [Google Scholar]
  38. Tartakovsky B., Kovacs E. J., Takacs L., Durum S. K. T cell clone producing an IL 1-like activity after stimulation by antigen-presenting B cells. J Immunol. 1986 Jul 1;137(1):160–166. [PubMed] [Google Scholar]
  39. Thompson C. B., Lindsten T., Ledbetter J. A., Kunkel S. L., Young H. A., Emerson S. G., Leiden J. M., June C. H. CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/cytokines. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1333–1337. doi: 10.1073/pnas.86.4.1333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Togawa A., Oppenheim J. J., Mizel S. B. Characterization of lymphocyte-activating factor (LAF) produced by human mononuclear cells: biochemical relationship of high and low molecular weight forms of LAF. J Immunol. 1979 May;122(5):2112–2118. [PubMed] [Google Scholar]
  41. Tony H. P., Phillips N. E., Parker D. C. Role of membrane immunoglobulin (Ig) crosslinking in membrane Ig-mediated, major histocompatibility-restricted T cell-B cell cooperation. J Exp Med. 1985 Nov 1;162(5):1695–1708. doi: 10.1084/jem.162.5.1695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Watson J. Continuous proliferation of murine antigen-specific helper T lymphocytes in culture. J Exp Med. 1979 Dec 1;150(6):1510–1519. doi: 10.1084/jem.150.6.1510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Weaver C. T., Hawrylowicz C. M., Unanue E. R. T helper cell subsets require the expression of distinct costimulatory signals by antigen-presenting cells. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8181–8185. doi: 10.1073/pnas.85.21.8181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Young J. W., Koulova L., Soergel S. A., Clark E. A., Steinman R. M., Dupont B. The B7/BB1 antigen provides one of several costimulatory signals for the activation of CD4+ T lymphocytes by human blood dendritic cells in vitro. J Clin Invest. 1992 Jul;90(1):229–237. doi: 10.1172/JCI115840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Zubiaga A. M., Muñoz E., Huber B. T. Production of IL-1 alpha by activated Th type 2 cells. Its role as an autocrine growth factor. J Immunol. 1991 Jun 1;146(11):3849–3856. [PubMed] [Google Scholar]

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