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. 1995 Nov 1;182(5):1591–1596. doi: 10.1084/jem.182.5.1591

Extent of T cell receptor ligation can determine the functional differentiation of naive CD4+ T cells

PMCID: PMC2192213  PMID: 7595230

Abstract

Naive CD4+ T cells can differentiate into cells predominantly involved in humoral immunity, known as T helper type 2 cells (Th2), or cells involved in cell-mediated immunity, known as Th1 cells. In this report, we show that priming of CD4+ T cells bearing a transgene-encoded T cell receptor can lead to differentiation into Th1-like cells producing abundant interferon gamma when the cells are exposed to high antigen doses, while low doses of the same peptide induce cells with the same T cell receptor to differentiate into Th2-like cells producing abundant interleukin 4. Thus antigen dose is one factor that can control the differentiation fate of a naive CD4+ T cell.

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Selected References

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  1. Betz M., Fox B. S. Regulation and development of cytochrome c-specific IL-4-producing T cells. J Immunol. 1990 Aug 15;145(4):1046–1052. [PubMed] [Google Scholar]
  2. Bottomly K., Luqman M., Greenbaum L., Carding S., West J., Pasqualini T., Murphy D. B. A monoclonal antibody to murine CD45R distinguishes CD4 T cell populations that produce different cytokines. Eur J Immunol. 1989 Apr;19(4):617–623. doi: 10.1002/eji.1830190407. [DOI] [PubMed] [Google Scholar]
  3. Bretscher P. A., Wei G., Menon J. N., Bielefeldt-Ohmann H. Establishment of stable, cell-mediated immunity that makes "susceptible" mice resistant to Leishmania major. Science. 1992 Jul 24;257(5069):539–542. doi: 10.1126/science.1636090. [DOI] [PubMed] [Google Scholar]
  4. Chatelain R., Varkila K., Coffman R. L. IL-4 induces a Th2 response in Leishmania major-infected mice. J Immunol. 1992 Feb 15;148(4):1182–1187. [PubMed] [Google Scholar]
  5. Clerici M., Shearer G. M. A TH1-->TH2 switch is a critical step in the etiology of HIV infection. Immunol Today. 1993 Mar;14(3):107–111. doi: 10.1016/0167-5699(93)90208-3. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Finkelman F. D., Pearce E. J., Urban J. F., Jr, Sher A. Regulation and biological function of helminth-induced cytokine responses. Immunol Today. 1991 Mar;12(3):A62–A66. doi: 10.1016/S0167-5699(05)80018-0. [DOI] [PubMed] [Google Scholar]
  8. Gajewski T. F., Fitch F. W. Anti-proliferative effect of IFN-gamma in immune regulation. I. IFN-gamma inhibits the proliferation of Th2 but not Th1 murine helper T lymphocyte clones. J Immunol. 1988 Jun 15;140(12):4245–4252. [PubMed] [Google Scholar]
  9. Heinzel F. P., Sadick M. D., Holaday B. J., Coffman R. L., Locksley R. M. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med. 1989 Jan 1;169(1):59–72. doi: 10.1084/jem.169.1.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kaye J., Hsu M. L., Sauron M. E., Jameson S. C., Gascoigne N. R., Hedrick S. M. Selective development of CD4+ T cells in transgenic mice expressing a class II MHC-restricted antigen receptor. Nature. 1989 Oct 26;341(6244):746–749. doi: 10.1038/341746a0. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. 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]
  13. Le Gros G., Ben-Sasson S. Z., Seder R., Finkelman F. D., Paul W. E. Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J Exp Med. 1990 Sep 1;172(3):921–929. doi: 10.1084/jem.172.3.921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Levin D., Constant S., Pasqualini T., Flavell R., Bottomly K. Role of dendritic cells in the priming of CD4+ T lymphocytes to peptide antigen in vivo. J Immunol. 1993 Dec 15;151(12):6742–6750. [PubMed] [Google Scholar]
  15. Mamula M. J., Janeway C. A., Jr Do B cells drive the diversification of immune responses? Immunol Today. 1993 Apr;14(4):151–154. doi: 10.1016/0167-5699(93)90274-O. [DOI] [PubMed] [Google Scholar]
  16. Manetti R., Parronchi P., Giudizi M. G., Piccinni M. P., Maggi E., Trinchieri G., Romagnani S. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med. 1993 Apr 1;177(4):1199–1204. doi: 10.1084/jem.177.4.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Miltenyi S., Müller W., Weichel W., Radbruch A. High gradient magnetic cell separation with MACS. Cytometry. 1990;11(2):231–238. doi: 10.1002/cyto.990110203. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Murray J. S., Madri J., Pasqualini T., Bottomly K. Functional CD4 T cell subset interplay in an intact immune system. J Immunol. 1993 May 15;150(10):4270–4276. [PubMed] [Google Scholar]
  20. Murray J. S., Madri J., Tite J., Carding S. R., Bottomly K. MHC control of CD4+ T cell subset activation. J Exp Med. 1989 Dec 1;170(6):2135–2140. doi: 10.1084/jem.170.6.2135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Parish C. R. Immune response to chemically modified flagellin. I. Induction of antibody tolerance to flagellin by acetoacetylated derivatives of the protein. J Exp Med. 1971 Jul 1;134(1):1–20. doi: 10.1084/jem.134.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Parronchi P., Macchia D., Piccinni M. P., Biswas P., Simonelli C., Maggi E., Ricci M., Ansari A. A., Romagnani S. Allergen- and bacterial antigen-specific T-cell clones established from atopic donors show a different profile of cytokine production. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4538–4542. doi: 10.1073/pnas.88.10.4538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Pfeiffer C., Murray J., Madri J., Bottomly K. Selective activation of Th1- and Th2-like cells in vivo--response to human collagen IV. Immunol Rev. 1991 Oct;123:65–84. doi: 10.1111/j.1600-065x.1991.tb00606.x. [DOI] [PubMed] [Google Scholar]
  24. Pfeiffer C., Stein J., Southwood S., Ketelaar H., Sette A., Bottomly K. Altered peptide ligands can control CD4 T lymphocyte differentiation in vivo. J Exp Med. 1995 Apr 1;181(4):1569–1574. doi: 10.1084/jem.181.4.1569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Salgame P., Abrams J. S., Clayberger C., Goldstein H., Convit J., Modlin R. L., Bloom B. R. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science. 1991 Oct 11;254(5029):279–282. doi: 10.1126/science.254.5029.279. [DOI] [PubMed] [Google Scholar]
  26. Seder R. A., Paul W. E., Davis M. M., Fazekas de St Groth B. The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice. J Exp Med. 1992 Oct 1;176(4):1091–1098. doi: 10.1084/jem.176.4.1091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sher A., Gazzinelli R. T., Oswald I. P., Clerici M., Kullberg M., Pearce E. J., Berzofsky J. A., Mosmann T. R., James S. L., Morse H. C., 3rd Role of T-cell derived cytokines in the downregulation of immune responses in parasitic and retroviral infection. Immunol Rev. 1992 Jun;127:183–204. doi: 10.1111/j.1600-065x.1992.tb01414.x. [DOI] [PubMed] [Google Scholar]
  28. Shivakumar S., Sercarz E. E., Krzych U. The molecular context of determinants within the priming antigen establishes a hierarchy of T cell induction: T cell specificities induced by peptides of beta-galactosidase vs. the whole antigen. Eur J Immunol. 1989 Apr;19(4):681–687. doi: 10.1002/eji.1830190417. [DOI] [PubMed] [Google Scholar]
  29. Sypek J. P., Chung C. L., Mayor S. E., Subramanyam J. M., Goldman S. J., Sieburth D. S., Wolf S. F., Schaub R. G. Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response. J Exp Med. 1993 Jun 1;177(6):1797–1802. doi: 10.1084/jem.177.6.1797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Urban J. F., Jr, Madden K. B., Svetić A., Cheever A., Trotta P. P., Gause W. C., Katona I. M., Finkelman F. D. The importance of Th2 cytokines in protective immunity to nematodes. Immunol Rev. 1992 Jun;127:205–220. doi: 10.1111/j.1600-065x.1992.tb01415.x. [DOI] [PubMed] [Google Scholar]

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