Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1988 Dec 1;168(6):2231–2249. doi: 10.1084/jem.168.6.2231

Involvement of the interleukin 2 pathway in the rearrangement and expression of both alpha/beta and gamma/delta T cell receptor genes in human T cell precursors

PMCID: PMC2189167  PMID: 2848921

Abstract

In this report, we have undertaken the phenotypic, functional and molecular characterization of a minor (less than 5%) subpopulation of adult thymocytes regarded as the earliest intrathymic T-cell precursors. Pro-T cells were immunoselected and shown to express different hematopoietic cell markers (CD45, CD38, CD7, CD5) and some activation-related molecules (4F2, Tr, HLA class II), but lack conventional T cell antigens (CD2-1-3-4-8-). TCR-gamma RNA messages are already expressed at this early ontogenic stage, while alpha and beta chain TCR genes remain in germline configuration. In vitro analyses of the growth requirements of pro-T cells demonstrated the involvement of the IL-2 pathway in promoting their proliferation and differentiation into CD3+ CD4+ or CD8+ mature thymocytes. Moreover, during the IL-2- mediated maturation process rearrangements and expression of both alpha and beta chain TCR genes occurred, and resulted in the acquisition of alpha/beta as well as gamma/delta (either disulphide-linked or non- disulphide-linked) heterodimeric TCR among the pro-T cell progeny.

Full Text

The Full Text of this article is available as a PDF (1.4 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Acuto O., Hussey R. E., Fitzgerald K. A., Protentis J. P., Meuer S. C., Schlossman S. F., Reinherz E. L. The human T cell receptor: appearance in ontogeny and biochemical relationship of alpha and beta subunits on IL-2 dependent clones and T cell tumors. Cell. 1983 Oct;34(3):717–726. doi: 10.1016/0092-8674(83)90528-7. [DOI] [PubMed] [Google Scholar]
  2. Adkins B., Mueller C., Okada C. Y., Reichert R. A., Weissman I. L., Spangrude G. J. Early events in T-cell maturation. Annu Rev Immunol. 1987;5:325–365. doi: 10.1146/annurev.iy.05.040187.001545. [DOI] [PubMed] [Google Scholar]
  3. Allison J. P., Lanier L. L. Structure, function, and serology of the T-cell antigen receptor complex. Annu Rev Immunol. 1987;5:503–540. doi: 10.1146/annurev.iy.05.040187.002443. [DOI] [PubMed] [Google Scholar]
  4. Bank I., DePinho R. A., Brenner M. B., Cassimeris J., Alt F. W., Chess L. A functional T3 molecule associated with a novel heterodimer on the surface of immature human thymocytes. Nature. 1986 Jul 10;322(6075):179–181. doi: 10.1038/322179a0. [DOI] [PubMed] [Google Scholar]
  5. Barnstable C. J., Bodmer W. F., Brown G., Galfre G., Milstein C., Williams A. F., Ziegler A. Production of monoclonal antibodies to group A erythrocytes, HLA and other human cell surface antigens-new tools for genetic analysis. Cell. 1978 May;14(1):9–20. doi: 10.1016/0092-8674(78)90296-9. [DOI] [PubMed] [Google Scholar]
  6. Born W., Yagüe J., Palmer E., Kappler J., Marrack P. Rearrangement of T-cell receptor beta-chain genes during T-cell development. Proc Natl Acad Sci U S A. 1985 May;82(9):2925–2929. doi: 10.1073/pnas.82.9.2925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Borst J., van Dongen J. J., Bolhuis R. L., Peters P. J., Hafler D. A., de Vries E., van de Griend R. J. Distinct molecular forms of human T cell receptor gamma/delta detected on viable T cells by a monoclonal antibody. J Exp Med. 1988 May 1;167(5):1625–1644. doi: 10.1084/jem.167.5.1625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Borst J., van de Griend R. J., van Oostveen J. W., Ang S. L., Melief C. J., Seidman J. G., Bolhuis R. L. A T-cell receptor gamma/CD3 complex found on cloned functional lymphocytes. Nature. 1987 Feb 19;325(6106):683–688. doi: 10.1038/325683a0. [DOI] [PubMed] [Google Scholar]
  9. Brenner M. B., McLean J., Dialynas D. P., Strominger J. L., Smith J. A., Owen F. L., Seidman J. G., Ip S., Rosen F., Krangel M. S. Identification of a putative second T-cell receptor. Nature. 1986 Jul 10;322(6075):145–149. doi: 10.1038/322145a0. [DOI] [PubMed] [Google Scholar]
  10. Brenner M. B., McLean J., Scheft H., Riberdy J., Ang S. L., Seidman J. G., Devlin P., Krangel M. S. Two forms of the T-cell receptor gamma protein found on peripheral blood cytotoxic T lymphocytes. Nature. 1987 Feb 19;325(6106):689–694. doi: 10.1038/325689a0. [DOI] [PubMed] [Google Scholar]
  11. Carrera A. C., Sanchez-Madrid F., Lopez-Botet M., Bernabeu C., De Landazuri M. O. Involvement of the CD4 molecule in a post-activation event on T cell proliferation. Eur J Immunol. 1987 Feb;17(2):179–186. doi: 10.1002/eji.1830170205. [DOI] [PubMed] [Google Scholar]
  12. Chien Y. H., Iwashima M., Kaplan K. B., Elliott J. F., Davis M. M. A new T-cell receptor gene located within the alpha locus and expressed early in T-cell differentiation. 1987 Jun 25-Jul 1Nature. 327(6124):677–682. doi: 10.1038/327677a0. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. De la Hera A., Toribio M. L., Marcos M. A., Marquez C., Martinez C. Interleukin 2 pathway is autonomously activated in human T11+3-4-6-8- thymocytes. Eur J Immunol. 1987 May;17(5):683–687. doi: 10.1002/eji.1830170516. [DOI] [PubMed] [Google Scholar]
  15. De la Hera A., Toribio M. L., Marquez C., Marcos M. A., Cabrero E., Martinez-A C. Differentiation of human mature thymocytes: existence of a T3+4-8- intermediate stage. Eur J Immunol. 1986 Jun;16(6):653–658. doi: 10.1002/eji.1830160611. [DOI] [PubMed] [Google Scholar]
  16. Eisenbarth G. S., Haynes B. F., Schroer J. A., Fauci A. S. Production of monoclonal antibodies reacting with peripheral blood mononuclear cell surface differentiation antigens. J Immunol. 1980 Mar;124(3):1237–1244. [PubMed] [Google Scholar]
  17. Fowlkes B. J., Edison L., Mathieson B. J., Chused T. M. Early T lymphocytes. Differentiation in vivo of adult intrathymic precursor cells. J Exp Med. 1985 Sep 1;162(3):802–822. doi: 10.1084/jem.162.3.802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hardt C., Diamantstein T., Wagner H. Developmentally controlled expression of IL 2 receptors and of sensitivity to IL 2 in a subset of embryonic thymocytes. J Immunol. 1985 Jun;134(6):3891–3894. [PubMed] [Google Scholar]
  19. Haskins K., Kubo R., White J., Pigeon M., Kappler J., Marrack P. The major histocompatibility complex-restricted antigen receptor on T cells. I. Isolation with a monoclonal antibody. J Exp Med. 1983 Apr 1;157(4):1149–1169. doi: 10.1084/jem.157.4.1149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hayday A. C., Saito H., Gillies S. D., Kranz D. M., Tanigawa G., Eisen H. N., Tonegawa S. Structure, organization, and somatic rearrangement of T cell gamma genes. Cell. 1985 Feb;40(2):259–269. doi: 10.1016/0092-8674(85)90140-0. [DOI] [PubMed] [Google Scholar]
  21. Jenkinson E. J., Kingston R., Owen J. J. Importance of IL-2 receptors in intra-thymic generation of cells expressing T-cell receptors. Nature. 1987 Sep 10;329(6135):160–162. doi: 10.1038/329160a0. [DOI] [PubMed] [Google Scholar]
  22. Lefranc M. P., Rabbitts T. H. Two tandemly organized human genes encoding the T-cell gamma constant-region sequences show multiple rearrangement in different T-cell types. Nature. 1985 Aug 1;316(6027):464–466. doi: 10.1038/316464a0. [DOI] [PubMed] [Google Scholar]
  23. Lew A. M., Pardoll D. M., Maloy W. L., Fowlkes B. J., Kruisbeek A., Cheng S. F., Germain R. N., Bluestone J. A., Schwartz R. H., Coligan J. E. Characterization of T cell receptor gamma chain expression in a subset of murine thymocytes. Science. 1986 Dec 12;234(4782):1401–1405. doi: 10.1126/science.3787252. [DOI] [PubMed] [Google Scholar]
  24. Lobach D. F., Haynes B. F. Ontogeny of the human thymus during fetal development. J Clin Immunol. 1987 Mar;7(2):81–97. doi: 10.1007/BF00916002. [DOI] [PubMed] [Google Scholar]
  25. Malissen B., Rebai N., Liabeuf A., Mawas C. Human cytotoxic T cell structures associated with expression of cytolysis. I. Analysis at the clonal cell level of the cytolysis-inhibiting effect of 7 monoclonal antibodies. Eur J Immunol. 1982 Sep;12(9):739–747. doi: 10.1002/eji.1830120908. [DOI] [PubMed] [Google Scholar]
  26. McMichael A. J., Pilch J. R., Galfré G., Mason D. Y., Fabre J. W., Milstein C. A human thymocyte antigen defined by a hybrid myeloma monoclonal antibody. Eur J Immunol. 1979 Mar;9(3):205–210. doi: 10.1002/eji.1830090307. [DOI] [PubMed] [Google Scholar]
  27. Meuer S. C., Fitzgerald K. A., Hussey R. E., Hodgdon J. C., Schlossman S. F., Reinherz E. L. Clonotypic structures involved in antigen-specific human T cell function. Relationship to the T3 molecular complex. J Exp Med. 1983 Feb 1;157(2):705–719. doi: 10.1084/jem.157.2.705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Palacios R., Kiefer M., Brockhaus M., Karjalainen K., Dembić Z., Kisielow P., von Boehmer H. Molecular, cellular, and functional properties of bone marrow T lymphocyte progenitor clones. J Exp Med. 1987 Jul 1;166(1):12–32. doi: 10.1084/jem.166.1.12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Palacios R., Von Boehmer H. Requirements for growth of immature thymocytes from fetal and adult mice in vitro. Eur J Immunol. 1986 Jan;16(1):12–19. doi: 10.1002/eji.1830160104. [DOI] [PubMed] [Google Scholar]
  30. Raulet D. H. Expression and function of interleukin-2 receptors on immature thymocytes. Nature. 1985 Mar 7;314(6006):101–103. doi: 10.1038/314101a0. [DOI] [PubMed] [Google Scholar]
  31. Raulet D. H., Garman R. D., Saito H., Tonegawa S. Developmental regulation of T-cell receptor gene expression. Nature. 1985 Mar 7;314(6006):103–107. doi: 10.1038/314103a0. [DOI] [PubMed] [Google Scholar]
  32. Roehm N., Herron L., Cambier J., DiGuisto D., Haskins K., Kappler J., Marrack P. The major histocompatibility complex-restricted antigen receptor on T cells: distribution on thymus and peripheral T cells. Cell. 1984 Sep;38(2):577–584. doi: 10.1016/0092-8674(84)90512-9. [DOI] [PubMed] [Google Scholar]
  33. Royer H. D., Acuto O., Fabbi M., Tizard R., Ramachandran K., Smart J. E., Reinherz E. L. Genes encoding the Ti beta subunit of the antigen/MHC receptor undergo rearrangement during intrathymic ontogeny prior to surface T3-Ti expression. Cell. 1984 Dec;39(2 Pt 1):261–266. doi: 10.1016/0092-8674(84)90003-5. [DOI] [PubMed] [Google Scholar]
  34. Royer H. D., Ramarli D., Acuto O., Campen T. J., Reinherz E. L. Genes encoding the T-cell receptor alpha and beta subunits are transcribed in an ordered manner during intrathymic ontogeny. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5510–5514. doi: 10.1073/pnas.82.16.5510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Shimonkevitz R. P., Husmann L. A., Bevan M. J., Crispe I. N. Transient expression of IL-2 receptor precedes the differentiation of immature thymocytes. Nature. 1987 Sep 10;329(6135):157–159. doi: 10.1038/329157a0. [DOI] [PubMed] [Google Scholar]
  36. Smith K. A. The bimolecular structure of the interleukin 2 receptor. Immunol Today. 1988 Feb;9(2):36–37. doi: 10.1016/0167-5699(88)91255-8. [DOI] [PubMed] [Google Scholar]
  37. Snodgrass H. R., Dembić Z., Steinmetz M., von Boehmer H. Expression of T-cell antigen receptor genes during fetal development in the thymus. Nature. 1985 May 16;315(6016):232–233. doi: 10.1038/315232a0. [DOI] [PubMed] [Google Scholar]
  38. Snodgrass H. R., Kisielow P., Kiefer M., Steinmetz M., von Boehmer H. Ontogeny of the T-cell antigen receptor within the thymus. Nature. 1985 Feb 14;313(6003):592–595. doi: 10.1038/313592a0. [DOI] [PubMed] [Google Scholar]
  39. Spits H., Borst J., Tax W., Capel P. J., Terhorst C., de Vries J. E. Characteristics of a monoclonal antibody (WT-31) that recognizes a common epitope on the human T cell receptor for antigen. J Immunol. 1985 Sep;135(3):1922–1928. [PubMed] [Google Scholar]
  40. Spits H., Yssel H., Leeuwenberg J., De Vries J. E. Antigen-specific cytotoxic T cell and antigen-specific proliferating T cell clones can be induced to cytolytic activity by monoclonal antibodies against T3. Eur J Immunol. 1985 Jan;15(1):88–91. doi: 10.1002/eji.1830150117. [DOI] [PubMed] [Google Scholar]
  41. Staerz U. D., Rammensee H. G., Benedetto J. D., Bevan M. J. Characterization of a murine monoclonal antibody specific for an allotypic determinant on T cell antigen receptor. J Immunol. 1985 Jun;134(6):3994–4000. [PubMed] [Google Scholar]
  42. Teshigawara K., Wang H. M., Kato K., Smith K. A. Interleukin 2 high-affinity receptor expression requires two distinct binding proteins. J Exp Med. 1987 Jan 1;165(1):223–238. doi: 10.1084/jem.165.1.223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Tidman N., Janossy G., Bodger M., Granger S., Kung P. C., Goldstein G. Delineation of human thymocyte differentiation pathways utilizing double-staining techniques with monoclonal antibodies. Clin Exp Immunol. 1981 Sep;45(3):457–467. [PMC free article] [PubMed] [Google Scholar]
  44. Toribio M. L., De Landázuri M. O., López-Botet M. Induction of natural killer-like cytotoxicity in cultured human thymocytes. Eur J Immunol. 1983 Dec;13(12):964–969. doi: 10.1002/eji.1830131203. [DOI] [PubMed] [Google Scholar]
  45. Toribio M. L., Martinez C., Marcos M. A., Marquez C., Cabrero E., de la Hera A. A role for T3+4-6-8- transitional thymocytes in the differentiation of mature and functional T cells from human prothymocytes. Proc Natl Acad Sci U S A. 1986 Sep;83(18):6985–6988. doi: 10.1073/pnas.83.18.6985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Toribio M. L., de la Hera A., Regueiro J. R., Márquez C., Marcos M. A., Bragado R., Arnaiz-Villena A., Martínez C. Alpha/beta heterodimeric T-cell receptor expression early in thymocyte differentiation. J Mol Cell Immunol. 1988;3(6):347–362. [PubMed] [Google Scholar]
  47. Tsudo M., Kozak R. W., Goldman C. K., Waldmann T. A. Demonstration of a non-Tac peptide that binds interleukin 2: a potential participant in a multichain interleukin 2 receptor complex. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9694–9698. doi: 10.1073/pnas.83.24.9694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Van Dongen J. J., Wolvers-Tettero I. L., Seidman J. G., Ang S. L., Van de Griend R. J., De Vries E. F., Borst J. Two types of gamma T cell receptors expressed by T cell acute lymphoblastic leukemias. Eur J Immunol. 1987 Dec;17(12):1719–1728. doi: 10.1002/eji.1830171207. [DOI] [PubMed] [Google Scholar]
  49. Waldmann T. A., Davis M. M., Bongiovanni K. F., Korsmeyer S. J. Rearrangements of genes for the antigen receptor on T cells as markers of lineage and clonality in human lymphoid neoplasms. N Engl J Med. 1985 Sep 26;313(13):776–783. doi: 10.1056/NEJM198509263131303. [DOI] [PubMed] [Google Scholar]
  50. Wang H. M., Smith K. A. The interleukin 2 receptor. Functional consequences of its bimolecular structure. J Exp Med. 1987 Oct 1;166(4):1055–1069. doi: 10.1084/jem.166.4.1055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Yanagi Y., Chan A., Chin B., Minden M., Mak T. W. Analysis of cDNA clones specific for human T cells and the alpha and beta chains of the T-cell receptor heterodimer from a human T-cell line. Proc Natl Acad Sci U S A. 1985 May;82(10):3430–3434. doi: 10.1073/pnas.82.10.3430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Yoshikai Y., Anatoniou D., Clark S. P., Yanagi Y., Sangster R., Van den Elsen P., Terhorst C., Mak T. W. Sequence and expression of transcripts of the human T-cell receptor beta-chain genes. Nature. 1984 Dec 6;312(5994):521–524. doi: 10.1038/312521a0. [DOI] [PubMed] [Google Scholar]
  53. Yoshikai Y., Toyonaga B., Koga Y., Kimura N., Griesser H., Mak T. W. Repertoire of the human T cell gamma genes: high frequency of nonfunctional transcripts in thymus and mature T cells. Eur J Immunol. 1987 Jan;17(1):119–126. doi: 10.1002/eji.1830170120. [DOI] [PubMed] [Google Scholar]
  54. de la Hera A., Toribio M. L., Marquez C., Martinez C. Interleukin 2 promotes growth and cytolytic activity in human T3+4-8- thymocytes. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6268–6271. doi: 10.1073/pnas.82.18.6268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. von Boehmer H., Crisanti A., Kisielow P., Haas W. Absence of growth by most receptor-expressing fetal thymocytes in the presence of interleukin-2. Nature. 1985 Apr 11;314(6011):539–540. doi: 10.1038/314539a0. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES