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. 1997 Mar 17;16(6):1360–1370. doi: 10.1093/emboj/16.6.1360

CD3 delta deficiency arrests development of the alpha beta but not the gamma delta T cell lineage.

V P Dave 1, Z Cao 1, C Browne 1, B Alarcon 1, G Fernandez-Miguel 1, J Lafaille 1, A de la Hera 1, S Tonegawa 1, D J Kappes 1
PMCID: PMC1169733  PMID: 9135151

Abstract

The CD3 complex found associated with the T cell receptor (TCR) is essential for signal transduction following TCR engagement. During T cell development, TCR-mediated signalling promotes the transition from one developmental stage to the next and controls whether a thymocyte undergoes positive or negative selection. The roles of particular CD3 components in these events remain unclear. Indeed, it is unknown whether they have specialized or overlapping roles. However, the multiplicity of CD3 components and their evolutionary conservation suggest that they serve distinct functions. Here the developmental requirement for the CD3 delta chain is analyzed by generating a mouse line specifically lacking this component (delta-/- mice). Strikingly, CD3 delta is shown to be differentially required during development. In particular, CD3 delta is not needed for steps in development mediated by pre-TCR or gamma delta TCR, but is required for further development of thymocytes expressing alpha beta TCR. Absence of CD3 delta specifically blocks the thymic selection processes that mediate the transition from the double-positive to single-positive stages of development.

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Selected References

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

  1. Alarcon B., Berkhout B., Breitmeyer J., Terhorst C. Assembly of the human T cell receptor-CD3 complex takes place in the endoplasmic reticulum and involves intermediary complexes between the CD3-gamma.delta.epsilon core and single T cell receptor alpha or beta chains. J Biol Chem. 1988 Feb 25;263(6):2953–2961. [PubMed] [Google Scholar]
  2. Aoe T., Okamoto Y., Arase H., Ikuta K., Miyazaki J., Ono S., Otuji M., Ohno H., Miyatake S., Saito T. Preferential requirement of CD3 zeta-mediated signals for development of immature rather than mature thymocytes. Int Immunol. 1996 Jul;8(7):1055–1066. doi: 10.1093/intimm/8.7.1055. [DOI] [PubMed] [Google Scholar]
  3. Baniyash M., Garcia-Morales P., Bonifacino J. S., Samelson L. E., Klausner R. D. Disulfide linkage of the zeta and eta chains of the T cell receptor. Possible identification of two structural classes of receptors. J Biol Chem. 1988 Jul 15;263(20):9874–9878. [PubMed] [Google Scholar]
  4. Blüthmann H., Kisielow P., Uematsu Y., Malissen M., Krimpenfort P., Berns A., von Boehmer H., Steinmetz M. T-cell-specific deletion of T-cell receptor transgenes allows functional rearrangement of endogenous alpha- and beta-genes. Nature. 1988 Jul 14;334(6178):156–159. doi: 10.1038/334156a0. [DOI] [PubMed] [Google Scholar]
  5. Bonifacino J. S., Suzuki C. K., Lippincott-Schwartz J., Weissman A. M., Klausner R. D. Pre-Golgi degradation of newly synthesized T-cell antigen receptor chains: intrinsic sensitivity and the role of subunit assembly. J Cell Biol. 1989 Jul;109(1):73–83. doi: 10.1083/jcb.109.1.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bonneville M., Ishida I., Itohara S., Verbeek S., Berns A., Kanagawa O., Haas W., Tonegawa S. Self-tolerance to transgenic gamma delta T cells by intrathymic inactivation. Nature. 1990 Mar 8;344(6262):163–165. doi: 10.1038/344163a0. [DOI] [PubMed] [Google Scholar]
  7. Brenner M. B., Trowbridge I. S., Strominger J. L. Cross-linking of human T cell receptor proteins: association between the T cell idiotype beta subunit and the T3 glycoprotein heavy subunit. Cell. 1985 Jan;40(1):183–190. doi: 10.1016/0092-8674(85)90321-6. [DOI] [PubMed] [Google Scholar]
  8. Brocker T., Karjalainen K. Signals through T cell receptor-zeta chain alone are insufficient to prime resting T lymphocytes. J Exp Med. 1995 May 1;181(5):1653–1659. doi: 10.1084/jem.181.5.1653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Buferne M., Luton F., Letourneur F., Hoeveler A., Couez D., Barad M., Malissen B., Schmitt-Verhulst A. M., Boyer C. Role of CD3 delta in surface expression of the TCR/CD3 complex and in activation for killing analyzed with a CD3 delta-negative cytotoxic T lymphocyte variant. J Immunol. 1992 Feb 1;148(3):657–664. [PubMed] [Google Scholar]
  10. Cambier J. C. Antigen and Fc receptor signaling. The awesome power of the immunoreceptor tyrosine-based activation motif (ITAM). J Immunol. 1995 Oct 1;155(7):3281–3285. [PubMed] [Google Scholar]
  11. Dent A. L., Matis L. A., Hooshmand F., Widacki S. M., Bluestone J. A., Hedrick S. M. Self-reactive gamma delta T cells are eliminated in the thymus. Nature. 1990 Feb 22;343(6260):714–719. doi: 10.1038/343714a0. [DOI] [PubMed] [Google Scholar]
  12. Dianzani U., Shaw A., al-Ramadi B. K., Kubo R. T., Janeway C. A., Jr Physical association of CD4 with the T cell receptor. J Immunol. 1992 Feb 1;148(3):678–688. [PubMed] [Google Scholar]
  13. Díez-Orejas R., Ballester S., Feito M. J., Ojeda G., Criado G., Ronda M., Portolés P., Rojo J. M. Genetic and immunochemical evidence for CD4-dependent association of p56lck with the alpha beta T-cell receptor (TCR): regulation of TCR-induced activation. EMBO J. 1994 Jan 1;13(1):90–99. doi: 10.1002/j.1460-2075.1994.tb06238.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Eshhar Z., Waks T., Gross G., Schindler D. G. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):720–724. doi: 10.1073/pnas.90.2.720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Exley M., Varticovski L., Peter M., Sancho J., Terhorst C. Association of phosphatidylinositol 3-kinase with a specific sequence of the T cell receptor zeta chain is dependent on T cell activation. J Biol Chem. 1994 May 27;269(21):15140–15146. [PubMed] [Google Scholar]
  16. Farace F., Angevin E., Vanderplancke J., Escudier B., Triebel F. The decreased expression of CD3 zeta chains in cancer patients is not reversed by IL-2 administration. Int J Cancer. 1994 Dec 15;59(6):752–755. doi: 10.1002/ijc.2910590607. [DOI] [PubMed] [Google Scholar]
  17. Festenstein R., Tolaini M., Corbella P., Mamalaki C., Parrington J., Fox M., Miliou A., Jones M., Kioussis D. Locus control region function and heterochromatin-induced position effect variegation. Science. 1996 Feb 23;271(5252):1123–1125. doi: 10.1126/science.271.5252.1123. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. 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]
  20. Hall C., Berkhout B., Alarcon B., Sancho J., Wileman T., Terhorst C. Requirements for cell surface expression of the human TCR/CD3 complex in non-T cells. Int Immunol. 1991 Apr;3(4):359–368. doi: 10.1093/intimm/3.4.359. [DOI] [PubMed] [Google Scholar]
  21. Isakov N., Wange R. L., Burgess W. H., Watts J. D., Aebersold R., Samelson L. E. ZAP-70 binding specificity to T cell receptor tyrosine-based activation motifs: the tandem SH2 domains of ZAP-70 bind distinct tyrosine-based activation motifs with varying affinity. J Exp Med. 1995 Jan 1;181(1):375–380. doi: 10.1084/jem.181.1.375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ito K., Van Kaer L., Bonneville M., Hsu S., Murphy D. B., Tonegawa S. Recognition of the product of a novel MHC TL region gene (27b) by a mouse gamma delta T cell receptor. Cell. 1990 Aug 10;62(3):549–561. doi: 10.1016/0092-8674(90)90019-b. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Kappes D. J., Tonegawa S. Surface expression of alternative forms of the TCR/CD3 complex. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10619–10623. doi: 10.1073/pnas.88.23.10619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kariv I., Hardy R. R., Hayakawa K. Two distinct non-T helper type 2 interleukin-4+ cell subsets in mice as revealed by single-cell cytokine analysis. Eur J Immunol. 1994 Mar;24(3):549–557. doi: 10.1002/eji.1830240309. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Kearse K. P., Roberts J. L., Munitz T. I., Wiest D. L., Nakayama T., Singer A. Developmental regulation of alpha beta T cell antigen receptor expression results from differential stability of nascent TCR alpha proteins within the endoplasmic reticulum of immature and mature T cells. EMBO J. 1994 Oct 3;13(19):4504–4514. doi: 10.1002/j.1460-2075.1994.tb06772.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kearse K. P., Roberts J. L., Singer A. TCR alpha-CD3 delta epsilon association is the initial step in alpha beta dimer formation in murine T cells and is limiting in immature CD4+ CD8+ thymocytes. Immunity. 1995 Apr;2(4):391–399. doi: 10.1016/1074-7613(95)90147-7. [DOI] [PubMed] [Google Scholar]
  29. Kisielow P., Blüthmann H., Staerz U. D., Steinmetz M., von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature. 1988 Jun 23;333(6175):742–746. doi: 10.1038/333742a0. [DOI] [PubMed] [Google Scholar]
  30. Koning F., Maloy W. L., Coligan J. E. The implications of subunit interactions for the structure of the T cell receptor-CD3 complex. Eur J Immunol. 1990 Feb;20(2):299–305. doi: 10.1002/eji.1830200211. [DOI] [PubMed] [Google Scholar]
  31. Krangel M. S., Bierer B. E., Devlin P., Clabby M., Strominger J. L., McLean J., Brenner M. B. T3 glycoprotein is functional although structurally distinct on human T-cell receptor gamma T lymphocytes. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3817–3821. doi: 10.1073/pnas.84.11.3817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ledermann B., Bürki K. Establishment of a germ-line competent C57BL/6 embryonic stem cell line. Exp Cell Res. 1991 Dec;197(2):254–258. doi: 10.1016/0014-4827(91)90430-3. [DOI] [PubMed] [Google Scholar]
  33. Malissen M., Gillet A., Ardouin L., Bouvier G., Trucy J., Ferrier P., Vivier E., Malissen B. Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene. EMBO J. 1995 Oct 2;14(19):4641–4653. doi: 10.1002/j.1460-2075.1995.tb00146.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Manolios N., Letourneur F., Bonifacino J. S., Klausner R. D. Pairwise, cooperative and inhibitory interactions describe the assembly and probable structure of the T-cell antigen receptor. EMBO J. 1991 Jul;10(7):1643–1651. doi: 10.1002/j.1460-2075.1991.tb07687.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Mizoguchi H., O'Shea J. J., Longo D. L., Loeffler C. M., McVicar D. W., Ochoa A. C. Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science. 1992 Dec 11;258(5089):1795–1798. doi: 10.1126/science.1465616. [DOI] [PubMed] [Google Scholar]
  36. Ohno H., Aoe T., Taki S., Kitamura D., Ishida Y., Rajewsky K., Saito T. Developmental and functional impairment of T cells in mice lacking CD3 zeta chains. EMBO J. 1993 Nov;12(11):4357–4366. doi: 10.1002/j.1460-2075.1993.tb06120.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Ono S., Ohno H., Saito T. Rapid turnover of the CD3 zeta chain independent of the TCR-CD3 complex in normal T cells. Immunity. 1995 Jun;2(6):639–644. doi: 10.1016/1074-7613(95)90008-x. [DOI] [PubMed] [Google Scholar]
  38. Osman N., Turner H., Lucas S., Reif K., Cantrell D. A. The protein interactions of the immunoglobulin receptor family tyrosine-based activation motifs present in the T cell receptor zeta subunits and the CD3 gamma, delta and epsilon chains. Eur J Immunol. 1996 May;26(5):1063–1068. doi: 10.1002/eji.1830260516. [DOI] [PubMed] [Google Scholar]
  39. 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]
  40. Pérez-Aciego P., Alarcón B., Arnaiz-Villena A., Terhorst C., Timón M., Segurado O. G., Regueiro J. R. Expression and function of a variant T cell receptor complex lacking CD3-gamma. J Exp Med. 1991 Aug 1;174(2):319–326. doi: 10.1084/jem.174.2.319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Ravichandran K. S., Lee K. K., Songyang Z., Cantley L. C., Burn P., Burakoff S. J. Interaction of Shc with the zeta chain of the T cell receptor upon T cell activation. Science. 1993 Nov 5;262(5135):902–905. doi: 10.1126/science.8235613. [DOI] [PubMed] [Google Scholar]
  42. Reth M. Antigen receptor tail clue. Nature. 1989 Mar 30;338(6214):383–384. doi: 10.1038/338383b0. [DOI] [PubMed] [Google Scholar]
  43. Romeo C., Amiot M., Seed B. Sequence requirements for induction of cytolysis by the T cell antigen/Fc receptor zeta chain. Cell. 1992 Mar 6;68(5):889–897. doi: 10.1016/0092-8674(92)90032-8. [DOI] [PubMed] [Google Scholar]
  44. Romeo C., Seed B. Cellular immunity to HIV activated by CD4 fused to T cell or Fc receptor polypeptides. Cell. 1991 Mar 8;64(5):1037–1046. doi: 10.1016/0092-8674(91)90327-u. [DOI] [PubMed] [Google Scholar]
  45. 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]
  46. Shores E. W., Huang K., Tran T., Lee E., Grinberg A., Love P. E. Role of TCR zeta chain in T cell development and selection. Science. 1994 Nov 11;266(5187):1047–1050. doi: 10.1126/science.7526464. [DOI] [PubMed] [Google Scholar]
  47. Sussman J. J., Bonifacino J. S., Lippincott-Schwartz J., Weissman A. M., Saito T., Klausner R. D., Ashwell J. D. Failure to synthesize the T cell CD3-zeta chain: structure and function of a partial T cell receptor complex. Cell. 1988 Jan 15;52(1):85–95. doi: 10.1016/0092-8674(88)90533-8. [DOI] [PubMed] [Google Scholar]
  48. Suzuki S., Kupsch J., Eichmann K., Saizawa M. K. Biochemical evidence of the physical association of the majority of CD3 delta chains with the accessory/co-receptor molecules CD4 and CD8 on nonactivated T lymphocytes. Eur J Immunol. 1992 Oct;22(10):2475–2479. doi: 10.1002/eji.1830221002. [DOI] [PubMed] [Google Scholar]
  49. Tuckett I. L. A CASE OF SIDEROSIS AFFECTING THE INNERVATION OF THE PUPIL. Br J Ophthalmol. 1918 Feb;2(2):79–82. doi: 10.1136/bjo.2.2.79. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Van Neerven J., Coligan J. E., Koning F. Structural comparison of alpha/beta and gamma/delta T cell receptor-CD3 complexes reveals identical subunit interactions but distinct cross-linking patterns of T cell receptor chains. Eur J Immunol. 1990 Sep;20(9):2105–2111. doi: 10.1002/eji.1830200932. [DOI] [PubMed] [Google Scholar]
  51. Wasserman R., Li Y. S., Hardy R. R. Differential expression of the blk and ret tyrosine kinases during B lineage development is dependent on Ig rearrangement. J Immunol. 1995 Jul 15;155(2):644–651. [PubMed] [Google Scholar]
  52. Wells F. B., Tatsumi Y., Bluestone J. A., Hedrick S. M., Allison J. P., Matis L. A. Phenotypic and functional analysis of positive selection in the gamma/delta T cell lineage. J Exp Med. 1993 Apr 1;177(4):1061–1070. doi: 10.1084/jem.177.4.1061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. de la Hera A., Müller U., Olsson C., Isaaz S., Tunnacliffe A. Structure of the T cell antigen receptor (TCR): two CD3 epsilon subunits in a functional TCR/CD3 complex. J Exp Med. 1991 Jan 1;173(1):7–17. doi: 10.1084/jem.173.1.7. [DOI] [PMC free article] [PubMed] [Google Scholar]

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