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. 1996 Nov 1;184(5):1833–1843. doi: 10.1084/jem.184.5.1833

Domains of the TCR beta-chain required for early thymocyte development

PMCID: PMC2192870  PMID: 8920871

Abstract

The T cell receptor beta (TCR beta) chain controls the developmental transition from CD4-CD8- to CD4+8+thymocytes. We show that the extracellular constant region and the transmembrane region, but not the variable domain or cytoplasmic tail of the TCR beta chain are required for this differentiation step. TCR beta mutant chains lacking the cytoplasmic tail can be found at the cell surface both in functional TCR/CD3 complexes and in a GPI-anchored monomeric form indicating that the cytoplasmic tail of the TCR beta chain functions as an ER retention signal. The concordance between cell surface expression of the mutant chains as TCR/CD3 complexes and their capacity to mediate thymocyte differentiation supports the CD3 mediated feedback model in which preTCR/CD3 complexes control the developmental transition from CD4-CD8- to CD4+CD8+thymocytes.

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Selected References

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  1. Ashwell J. D., Klusner R. D. Genetic and mutational analysis of the T-cell antigen receptor. Annu Rev Immunol. 1990;8:139–167. doi: 10.1146/annurev.iy.08.040190.001035. [DOI] [PubMed] [Google Scholar]
  2. Brouns G. S., de Vries E., van Noesel C. J., Mason D. Y., van Lier R. A., Borst J. The structure of the mu/pseudo light chain complex on human pre-B cells is consistent with a function in signal transduction. Eur J Immunol. 1993 May;23(5):1088–1097. doi: 10.1002/eji.1830230517. [DOI] [PubMed] [Google Scholar]
  3. Chen J., Young F., Bottaro A., Stewart V., Smith R. K., Alt F. W. Mutations of the intronic IgH enhancer and its flanking sequences differentially affect accessibility of the JH locus. EMBO J. 1993 Dec;12(12):4635–4645. doi: 10.1002/j.1460-2075.1993.tb06152.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chien Y. H., Gascoigne N. R., Kavaler J., Lee N. E., Davis M. M. Somatic recombination in a murine T-cell receptor gene. Nature. 1984 May 24;309(5966):322–326. doi: 10.1038/309322a0. [DOI] [PubMed] [Google Scholar]
  5. Cuypers H. T., Selten G., Quint W., Zijlstra M., Maandag E. R., Boelens W., van Wezenbeek P., Melief C., Berns A. Murine leukemia virus-induced T-cell lymphomagenesis: integration of proviruses in a distinct chromosomal region. Cell. 1984 May;37(1):141–150. doi: 10.1016/0092-8674(84)90309-x. [DOI] [PubMed] [Google Scholar]
  6. Davis M. M., Bjorkman P. J. T-cell antigen receptor genes and T-cell recognition. Nature. 1988 Aug 4;334(6181):395–402. doi: 10.1038/334395a0. [DOI] [PubMed] [Google Scholar]
  7. Dodemont H. J., Soriano P., Quax W. J., Ramaekers F., Lenstra J. A., Groenen M. A., Bernardi G., Bloemendal H. The genes coding for the cytoskeletal proteins actin and vimentin in warm-blooded vertebrates. EMBO J. 1982;1(2):167–171. doi: 10.1002/j.1460-2075.1982.tb01142.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fehling H. J., Krotkova A., Saint-Ruf C., von Boehmer H. Crucial role of the pre-T-cell receptor alpha gene in development of alpha beta but not gamma delta T cells. Nature. 1995 Jun 29;375(6534):795–798. doi: 10.1038/375795a0. [DOI] [PubMed] [Google Scholar]
  9. Ferrier P., Krippl B., Blackwell T. K., Furley A. J., Suh H., Winoto A., Cook W. D., Hood L., Costantini F., Alt F. W. Separate elements control DJ and VDJ rearrangement in a transgenic recombination substrate. EMBO J. 1990 Jan;9(1):117–125. doi: 10.1002/j.1460-2075.1990.tb08087.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Freitas A. A., Andrade L., Lembezat M. P., Coutinho A. Selection of VH gene repertoires: differentiating B cells of adult bone marrow mimic fetal development. Int Immunol. 1990;2(1):15–23. doi: 10.1093/intimm/2.1.15. [DOI] [PubMed] [Google Scholar]
  11. Furley A. J., Mizutani S., Weilbaecher K., Dhaliwal H. S., Ford A. M., Chan L. C., Molgaard H. V., Toyonaga B., Mak T., van den Elsen P. Developmentally regulated rearrangement and expression of genes encoding the T cell receptor-T3 complex. Cell. 1986 Jul 4;46(1):75–87. doi: 10.1016/0092-8674(86)90861-5. [DOI] [PubMed] [Google Scholar]
  12. Groettrup M., Baron A., Griffiths G., Palacios R., von Boehmer H. T cell receptor (TCR) beta chain homodimers on the surface of immature but not mature alpha, gamma, delta chain deficient T cell lines. EMBO J. 1992 Jul;11(7):2735–2745. doi: 10.1002/j.1460-2075.1992.tb05339.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Groettrup M., Ungewiss K., Azogui O., Palacios R., Owen M. J., Hayday A. C., von Boehmer H. A novel disulfide-linked heterodimer on pre-T cells consists of the T cell receptor beta chain and a 33 kd glycoprotein. Cell. 1993 Oct 22;75(2):283–294. doi: 10.1016/0092-8674(93)80070-u. [DOI] [PubMed] [Google Scholar]
  14. Haskins K., Hannum C., White J., Roehm N., Kubo R., Kappler J., Marrack P. The antigen-specific, major histocompatibility complex-restricted receptor on T cells. VI. An antibody to a receptor allotype. J Exp Med. 1984 Aug 1;160(2):452–471. doi: 10.1084/jem.160.2.452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hedrick S. M., Nielsen E. A., Kavaler J., Cohen D. I., Davis M. M. Sequence relationships between putative T-cell receptor polypeptides and immunoglobulins. Nature. 1984 Mar 8;308(5955):153–158. doi: 10.1038/308153a0. [DOI] [PubMed] [Google Scholar]
  16. Jackson M. R., Nilsson T., Peterson P. A. Identification of a consensus motif for retention of transmembrane proteins in the endoplasmic reticulum. EMBO J. 1990 Oct;9(10):3153–3162. doi: 10.1002/j.1460-2075.1990.tb07513.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Jacobs H., Vandeputte D., Tolkamp L., de Vries E., Borst J., Berns A. CD3 components at the surface of pro-T cells can mediate pre-T cell development in vivo. Eur J Immunol. 1994 Apr;24(4):934–939. doi: 10.1002/eji.1830240423. [DOI] [PubMed] [Google Scholar]
  18. Karasuyama H., Kudo A., Melchers F. The proteins encoded by the VpreB and lambda 5 pre-B cell-specific genes can associate with each other and with mu heavy chain. J Exp Med. 1990 Sep 1;172(3):969–972. doi: 10.1084/jem.172.3.969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kishi H., Borgulya P., Scott B., Karjalainen K., Traunecker A., Kaufman J., von Boehmer H. Surface expression of the beta T cell receptor (TCR) chain in the absence of other TCR or CD3 proteins on immature T cells. EMBO J. 1991 Jan;10(1):93–100. doi: 10.1002/j.1460-2075.1991.tb07924.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Klausner R. D., Lippincott-Schwartz J., Bonifacino J. S. The T cell antigen receptor: insights into organelle biology. Annu Rev Cell Biol. 1990;6:403–431. doi: 10.1146/annurev.cb.06.110190.002155. [DOI] [PubMed] [Google Scholar]
  21. Krimpenfort P., Ossendorp F., Borst J., Melief C., Berns A. T cell depletion in transgenic mice carrying a mutant gene for TCR-beta. Nature. 1989 Oct 26;341(6244):742–746. doi: 10.1038/341742a0. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Lafaille J. J., Nagashima K., Katsuki M., Tonegawa S. High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice. Cell. 1994 Aug 12;78(3):399–408. doi: 10.1016/0092-8674(94)90419-7. [DOI] [PubMed] [Google Scholar]
  24. Lai E., Barth R. K., Hood L. Genomic organization of the mouse T-cell receptor beta-chain gene family. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3846–3850. doi: 10.1073/pnas.84.11.3846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Laird P. W., Zijderveld A., Linders K., Rudnicki M. A., Jaenisch R., Berns A. Simplified mammalian DNA isolation procedure. Nucleic Acids Res. 1991 Aug 11;19(15):4293–4293. doi: 10.1093/nar/19.15.4293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Lauster R., Reynaud C. A., Mårtensson I. L., Peter A., Bucchini D., Jami J., Weill J. C. Promoter, enhancer and silencer elements regulate rearrangement of an immunoglobulin transgene. EMBO J. 1993 Dec;12(12):4615–4623. doi: 10.1002/j.1460-2075.1993.tb06150.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Leo O., Foo M., Sachs D. H., Samelson L. E., Bluestone J. A. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1374–1378. doi: 10.1073/pnas.84.5.1374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Levelt C. N., Mombaerts P., Iglesias A., Tonegawa S., Eichmann K. Restoration of early thymocyte differentiation in T-cell receptor beta-chain-deficient mutant mice by transmembrane signaling through CD3 epsilon. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11401–11405. doi: 10.1073/pnas.90.23.11401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mombaerts P., Clarke A. R., Rudnicki M. A., Iacomini J., Itohara S., Lafaille J. J., Wang L., Ichikawa Y., Jaenisch R., Hooper M. L. Mutations in T-cell antigen receptor genes alpha and beta block thymocyte development at different stages. Nature. 1992 Nov 19;360(6401):225–231. doi: 10.1038/360225a0. [DOI] [PubMed] [Google Scholar]
  30. Mombaerts P., Iacomini J., Johnson R. S., Herrup K., Tonegawa S., Papaioannou V. E. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992 Mar 6;68(5):869–877. doi: 10.1016/0092-8674(92)90030-g. [DOI] [PubMed] [Google Scholar]
  31. Nilsson T., Jackson M., Peterson P. A. Short cytoplasmic sequences serve as retention signals for transmembrane proteins in the endoplasmic reticulum. Cell. 1989 Aug 25;58(4):707–718. doi: 10.1016/0092-8674(89)90105-0. [DOI] [PubMed] [Google Scholar]
  32. Ossendorp F., Jacobs H., van der Horst G., de Vries E., Berns A., Borst J. T cell receptor-alpha beta lacking the beta-chain V domain can be expressed at the cell surface but prohibits T cell maturation. J Immunol. 1992 Jun 15;148(12):3714–3722. [PubMed] [Google Scholar]
  33. Payne J., Huber B. T., Cannon N. A., Schneider R., Schilham M. W., Acha-Orbea H., MacDonald H. R., Hengartner H. Two monoclonal rat antibodies with specificity for the beta-chain variable region V beta 6 of the murine T-cell receptor. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7695–7698. doi: 10.1073/pnas.85.20.7695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Perlmutter R. M., Kearney J. F., Chang S. P., Hood L. E. Developmentally controlled expression of immunoglobulin VH genes. Science. 1985 Mar 29;227(4694):1597–1601. doi: 10.1126/science.3975629. [DOI] [PubMed] [Google Scholar]
  35. Philpott K. L., Viney J. L., Kay G., Rastan S., Gardiner E. M., Chae S., Hayday A. C., Owen M. J. Lymphoid development in mice congenitally lacking T cell receptor alpha beta-expressing cells. Science. 1992 Jun 5;256(5062):1448–1452. doi: 10.1126/science.1604321. [DOI] [PubMed] [Google Scholar]
  36. Pillai S., Baltimore D. Formation of disulphide-linked mu 2 omega 2 tetramers in pre-B cells by the 18K omega-immunoglobulin light chain. Nature. 1987 Sep 10;329(6135):172–174. doi: 10.1038/329172a0. [DOI] [PubMed] [Google Scholar]
  37. Punt J. A., Kubo R. T., Saito T., Finkel T. H., Kathiresan S., Blank K. J., Hashimoto Y. Surface expression of a T cell receptor beta (TCR-beta) chain in the absence of TCR-alpha, -delta, and -gamma proteins. J Exp Med. 1991 Oct 1;174(4):775–783. doi: 10.1084/jem.174.4.775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Saint-Ruf C., Ungewiss K., Groettrup M., Bruno L., Fehling H. J., von Boehmer H. Analysis and expression of a cloned pre-T cell receptor gene. Science. 1994 Nov 18;266(5188):1208–1212. doi: 10.1126/science.7973703. [DOI] [PubMed] [Google Scholar]
  39. Saito H., Kranz D. M., Takagaki Y., Hayday A. C., Eisen H. N., Tonegawa S. A third rearranged and expressed gene in a clone of cytotoxic T lymphocytes. Nature. 1984 Nov 1;312(5989):36–40. doi: 10.1038/312036a0. [DOI] [PubMed] [Google Scholar]
  40. Serwe M., Sablitzky F. V(D)J recombination in B cells is impaired but not blocked by targeted deletion of the immunoglobulin heavy chain intron enhancer. EMBO J. 1993 Jun;12(6):2321–2327. doi: 10.1002/j.1460-2075.1993.tb05886.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Shinkai Y., Alt F. W. CD3 epsilon-mediated signals rescue the development of CD4+CD8+ thymocytes in RAG-2-/- mice in the absence of TCR beta chain expression. Int Immunol. 1994 Jul;6(7):995–1001. doi: 10.1093/intimm/6.7.995. [DOI] [PubMed] [Google Scholar]
  42. Shinkai Y., Koyasu S., Nakayama K., Murphy K. M., Loh D. Y., Reinherz E. L., Alt F. W. Restoration of T cell development in RAG-2-deficient mice by functional TCR transgenes. Science. 1993 Feb 5;259(5096):822–825. doi: 10.1126/science.8430336. [DOI] [PubMed] [Google Scholar]
  43. Shinkai Y., Rathbun G., Lam K. P., Oltz E. M., Stewart V., Mendelsohn M., Charron J., Datta M., Young F., Stall A. M. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992 Mar 6;68(5):855–867. doi: 10.1016/0092-8674(92)90029-c. [DOI] [PubMed] [Google Scholar]
  44. 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]
  45. Tsubata T., Reth M. The products of pre-B cell-specific genes (lambda 5 and VpreB) and the immunoglobulin mu chain form a complex that is transported onto the cell surface. J Exp Med. 1990 Sep 1;172(3):973–976. doi: 10.1084/jem.172.3.973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Uematsu Y., Ryser S., Dembić Z., Borgulya P., Krimpenfort P., Berns A., von Boehmer H., Steinmetz M. In transgenic mice the introduced functional T cell receptor beta gene prevents expression of endogenous beta genes. Cell. 1988 Mar 25;52(6):831–841. doi: 10.1016/0092-8674(88)90425-4. [DOI] [PubMed] [Google Scholar]
  47. Wilson R. K., Lai E., Concannon P., Barth R. K., Hood L. E. Structure, organization and polymorphism of murine and human T-cell receptor alpha and beta chain gene families. Immunol Rev. 1988 Jan;101:149–172. doi: 10.1111/j.1600-065x.1988.tb00736.x. [DOI] [PubMed] [Google Scholar]
  48. Yancopoulos G. D., Alt F. W. Developmentally controlled and tissue-specific expression of unrearranged VH gene segments. Cell. 1985 Feb;40(2):271–281. doi: 10.1016/0092-8674(85)90141-2. [DOI] [PubMed] [Google Scholar]
  49. Yancopoulos G. D., Desiderio S. V., Paskind M., Kearney J. F., Baltimore D., Alt F. W. Preferential utilization of the most JH-proximal VH gene segments in pre-B-cell lines. Nature. 1984 Oct 25;311(5988):727–733. doi: 10.1038/311727a0. [DOI] [PubMed] [Google Scholar]
  50. Yancopoulos G. D., Malynn B. A., Alt F. W. Developmentally regulated and strain-specific expression of murine VH gene families. J Exp Med. 1988 Jul 1;168(1):417–435. doi: 10.1084/jem.168.1.417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. von Boehmer H. Developmental biology of T cells in T cell-receptor transgenic mice. Annu Rev Immunol. 1990;8:531–556. doi: 10.1146/annurev.iy.08.040190.002531. [DOI] [PubMed] [Google Scholar]

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