Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1990 Jun 1;171(6):1981–1999. doi: 10.1084/jem.171.6.1981

Spontaneous loss and alteration of antigen receptor expression in mature CD4+ T cells

PMCID: PMC2187968  PMID: 1972177

Abstract

The TCR/CD3 complex plays a central role in antigen recognition and activation of mature T cells, and, therefore, abnormalities in the expression of the complex should induce unresponsiveness of T cells to antigen stimulus. Using flow cytometry, we detected and enumerated variant cells with loss or alteration of the surface TCR/CD3 expression among human mature CD4+ T cells. The presence of variant CD4+ T cells was demonstrated by isolating and cloning them from peripheral blood, and their abnormalities can be accounted for by alterations in TCR expression such as defects of protein expression and partial protein deletion. The variant frequency in peripheral blood increased with aging in normal donors and was highly elevated in patients with ataxia telangiectasia, an autosomal recessive inherited disease with defective DNA repair and variable T cell immunodeficiency. These findings suggest that such alterations in TCR expression are induced by somatic mutagenesis of TCR genes and can be important factors related to age- dependent and genetic disease-associated T cell dysfunction.

Full Text

The Full Text of this article is available as a PDF (1.3 MB).

Selected References

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

  1. Adetugbo K., Milstein C., Secher D. S. Molecular analysis of spontaneous somatic mutants. Nature. 1977 Jan 27;265(5592):299–304. doi: 10.1038/265299a0. [DOI] [PubMed] [Google Scholar]
  2. Albertini R. J., Castle K. L., Borcherding W. R. T-cell cloning to detect the mutant 6-thioguanine-resistant lymphocytes present in human peripheral blood. Proc Natl Acad Sci U S A. 1982 Nov;79(21):6617–6621. doi: 10.1073/pnas.79.21.6617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Alcover A., Alberini C., Acuto O., Clayton L. K., Transy C., Spagnoli G. C., Moingeon P., Lopez P., Reinherz E. L. Interdependence of CD3-Ti and CD2 activation pathways in human T lymphocytes. EMBO J. 1988 Jul;7(7):1973–1977. doi: 10.1002/j.1460-2075.1988.tb03035.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Allison J. P., McIntyre B. W., Bloch D. Tumor-specific antigen of murine T-lymphoma defined with monoclonal antibody. J Immunol. 1982 Nov;129(5):2293–2300. [PubMed] [Google Scholar]
  5. Arlett C. F., Lehmann A. R. Human disorders showing increased sensitivity to the induction of genetic damage. Annu Rev Genet. 1978;12:95–115. doi: 10.1146/annurev.ge.12.120178.000523. [DOI] [PubMed] [Google Scholar]
  6. Aurias A., Dutrillaux B., Buriot D., Lejeune J. High frequencies of inversions and translocations of chromosomes 7 and 14 in ataxia telangiectasia. Mutat Res. 1980 Feb;69(2):369–374. doi: 10.1016/0027-5107(80)90101-3. [DOI] [PubMed] [Google Scholar]
  7. Band H., Hochstenbach F., McLean J., Hata S., Krangel M. S., Brenner M. B. Immunochemical proof that a novel rearranging gene encodes the T cell receptor delta subunit. Science. 1987 Oct 30;238(4827):682–684. doi: 10.1126/science.3672118. [DOI] [PubMed] [Google Scholar]
  8. Baumal R., Birshtein B. K., Coffino P., Scharff M. D. Mutations in immunoglobulin-producing mouse myeloma cells. Science. 1973 Oct 12;182(4108):164–166. doi: 10.1126/science.182.4108.164. [DOI] [PubMed] [Google Scholar]
  9. Bigbee W. L., Langlois R. G., Swift M., Jensen R. H. Evidence for an elevated frequency of in vivo somatic cell mutations in ataxia telangiectasia. Am J Hum Genet. 1989 Mar;44(3):402–408. [PMC free article] [PubMed] [Google Scholar]
  10. Bockenstedt L. K., Goldsmith M. A., Dustin M., Olive D., Springer T. A., Weiss A. The CD2 ligand LFA-3 activates T cells but depends on the expression and function of the antigen receptor. J Immunol. 1988 Sep 15;141(6):1904–1911. [PubMed] [Google Scholar]
  11. Borst J., Alexander S., Elder J., Terhorst C. The T3 complex on human T lymphocytes involves four structurally distinct glycoproteins. J Biol Chem. 1983 Apr 25;258(8):5135–5141. [PubMed] [Google Scholar]
  12. 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]
  13. 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]
  14. Boutin B., Wagner D. K., Nelson D. L. Analysis of CD3 antigen expression in patients with ataxia-telangiectasia. Clin Exp Immunol. 1987 May;68(2):320–330. [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. Brenner M. B., McLean J., Scheft H., Warnke R. A., Jones N., Strominger J. L. Characterization and expression of the human alpha beta T cell receptor by using a framework monoclonal antibody. J Immunol. 1987 Mar 1;138(5):1502–1509. [PubMed] [Google Scholar]
  17. Brown M. H., Cantrell D. A., Brattsand G., Crumpton M. J., Gullberg M. The CD2 antigen associates with the T-cell antigen receptor CD3 antigen complex on the surface of human T lymphocytes. Nature. 1989 Jun 15;339(6225):551–553. doi: 10.1038/339551a0. [DOI] [PubMed] [Google Scholar]
  18. Clevers H., Alarcon B., Wileman T., Terhorst C. The T cell receptor/CD3 complex: a dynamic protein ensemble. Annu Rev Immunol. 1988;6:629–662. doi: 10.1146/annurev.iy.06.040188.003213. [DOI] [PubMed] [Google Scholar]
  19. Coffino P., Scharff M. D. Rate of somatic mutation in immunoglobulin production by mouse myeloma cells. Proc Natl Acad Sci U S A. 1971 Jan;68(1):219–223. doi: 10.1073/pnas.68.1.219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Cook W. D., Scharff M. D. Antigen-binding mutants of mouse myeloma cells. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5687–5691. doi: 10.1073/pnas.74.12.5687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Dunnick W., Rabbitts T. H., Milstein C. An immunoglobulin deletion mutant with implications for the heavy-chain switch and RNA splicing. Nature. 1980 Aug 14;286(5774):669–675. doi: 10.1038/286669a0. [DOI] [PubMed] [Google Scholar]
  22. Goodman T., Lefrançois L. Expression of the gamma-delta T-cell receptor on intestinal CD8+ intraepithelial lymphocytes. Nature. 1988 Jun 30;333(6176):855–858. doi: 10.1038/333855a0. [DOI] [PubMed] [Google Scholar]
  23. Groh V., Porcelli S., Fabbi M., Lanier L. L., Picker L. J., Anderson T., Warnke R. A., Bhan A. K., Strominger J. L., Brenner M. B. Human lymphocytes bearing T cell receptor gamma/delta are phenotypically diverse and evenly distributed throughout the lymphoid system. J Exp Med. 1989 Apr 1;169(4):1277–1294. doi: 10.1084/jem.169.4.1277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hakoda M., Akiyama M., Kyoizumi S., Kobuke K., Awa A. A., Yamakido M. Measurement of in vivo HGPRT-deficient mutant cell frequency using a modified method for cloning human peripheral blood T-lymphocytes. Mutat Res. 1988 Jan;197(1):161–169. doi: 10.1016/0027-5107(88)90153-4. [DOI] [PubMed] [Google Scholar]
  25. Hakoda M., Hirai Y., Shimba H., Kusunoki Y., Kyoizumi S., Kodama Y., Akiyama M. Cloning of phenotypically different human lymphocytes originating from a single stem cell. J Exp Med. 1989 Apr 1;169(4):1265–1276. doi: 10.1084/jem.169.4.1265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. 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]
  27. Hecht F., McCaw B. K., Koler R. D. Ataxia-telangiectasia--clonal growth of translocation lymphocytes. N Engl J Med. 1973 Aug 9;289(6):286–291. doi: 10.1056/NEJM197308092890603. [DOI] [PubMed] [Google Scholar]
  28. Heppell A., Butterworth S. V., Hollis R. J., Kennaugh A. A., Beatty D. W., Taylor A. M. Breakage of the T cell receptor alpha chain locus in non malignant clones from patients with ataxia telangiectasia. Hum Genet. 1988 Aug;79(4):360–364. doi: 10.1007/BF00282177. [DOI] [PubMed] [Google Scholar]
  29. Hochstenbach F., Parker C., McLean J., Gieselmann V., Band H., Bank I., Chess L., Spits H., Strominger J. L., Seidman J. G. Characterization of a third form of the human T cell receptor gamma/delta. J Exp Med. 1988 Aug 1;168(2):761–776. doi: 10.1084/jem.168.2.761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Janatipour M., Trainor K. J., Kutlaca R., Bennett G., Hay J., Turner D. R., Morley A. A. Mutations in human lymphocytes studied by an HLA selection system. Mutat Res. 1988 Mar;198(1):221–226. doi: 10.1016/0027-5107(88)90058-9. [DOI] [PubMed] [Google Scholar]
  31. Jäck H. M., Wabl M. High rates of deletions in the constant region segment of the immunoglobulin mu gene. Proc Natl Acad Sci U S A. 1987 Jul;84(14):4934–4938. doi: 10.1073/pnas.84.14.4934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Kinnon C., Diamond R. A., Rothenberg E. V. Activation of T cell antigen receptor alpha- and beta-chain genes in the thymus: implications for the lineages of developing cortical thymocytes. J Immunol. 1986 Dec 15;137(12):4010–4015. [PubMed] [Google Scholar]
  33. Kipps T. J., Parham P., Punt J., Herzenberg L. A. Importance of immunoglobulin isotype in human antibody-dependent, cell-mediated cytotoxicity directed by murine monoclonal antibodies. J Exp Med. 1985 Jan 1;161(1):1–17. doi: 10.1084/jem.161.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Kronenberg M., Siu G., Hood L. E., Shastri N. The molecular genetics of the T-cell antigen receptor and T-cell antigen recognition. Annu Rev Immunol. 1986;4:529–591. doi: 10.1146/annurev.iy.04.040186.002525. [DOI] [PubMed] [Google Scholar]
  35. Kyoizumi S., Akiyama M., Kouno N., Kobuke K., Hakoda M., Jones S. L., Yamakido M. Monoclonal antibodies to human squamous cell carcinoma of the lung and their application to tumor diagnosis. Cancer Res. 1985 Jul;45(7):3274–3281. [PubMed] [Google Scholar]
  36. Kyoizumi S., Nakamura N., Hakoda M., Awa A. A., Bean M. A., Jensen R. H., Akiyama M. Detection of somatic mutations at the glycophorin A locus in erythrocytes of atomic bomb survivors using a single beam flow sorter. Cancer Res. 1989 Feb 1;49(3):581–588. [PubMed] [Google Scholar]
  37. Langlois R. G., Bigbee W. L., Jensen R. H. Measurements of the frequency of human erythrocytes with gene expression loss phenotypes at the glycophorin A locus. Hum Genet. 1986 Dec;74(4):353–362. doi: 10.1007/BF00280485. [DOI] [PubMed] [Google Scholar]
  38. Langlois R. G., Bigbee W. L., Kyoizumi S., Nakamura N., Bean M. A., Akiyama M., Jensen R. H. Evidence for increased somatic cell mutations at the glycophorin A locus in atomic bomb survivors. Science. 1987 Apr 24;236(4800):445–448. doi: 10.1126/science.3563520. [DOI] [PubMed] [Google Scholar]
  39. Leder P., Battey J., Lenoir G., Moulding C., Murphy W., Potter H., Stewart T., Taub R. Translocations among antibody genes in human cancer. Science. 1983 Nov 18;222(4625):765–771. doi: 10.1126/science.6356357. [DOI] [PubMed] [Google Scholar]
  40. 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]
  41. Maecker H. T., Levy R. Spontaneous T cell antigen receptor variants of a human T leukemia cell line. J Immunol. 1988 Nov 1;141(9):2994–3002. [PubMed] [Google Scholar]
  42. Makinodan T., Kay M. M. Age influence on the immune system. Adv Immunol. 1980;29:287–330. doi: 10.1016/s0065-2776(08)60047-4. [DOI] [PubMed] [Google Scholar]
  43. Marolleau J. P., Fondell J. D., Malissen M., Trucy J., Barbier E., Marcu K. B., Cazenave P. A., Primi D. The joining of germ-line V alpha to J alpha genes replaces the preexisting V alpha-J alpha complexes in a T cell receptor alpha, beta positive T cell line. Cell. 1988 Oct 21;55(2):291–300. doi: 10.1016/0092-8674(88)90052-9. [DOI] [PubMed] [Google Scholar]
  44. McFarlin D. E., Oppenheim J. J. Impaired lymphocyte transformation in ataxia-telangiectasia in part due to a plasma inhibitory factor. J Immunol. 1969 Dec;103(6):1212–1222. [PubMed] [Google Scholar]
  45. McKean D., Huppi K., Bell M., Staudt L., Gerhard W., Weigert M. Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutinin. Proc Natl Acad Sci U S A. 1984 May;81(10):3180–3184. doi: 10.1073/pnas.81.10.3180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. 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]
  47. Moretta A., Poggi A., Olive D., Bottino C., Fortis C., Pantaleo G., Moretta L. Selection and characterization of T-cell variants lacking molecules involved in T-cell activation (T3 T-cell receptor, T44, and T11): analysis of the functional relationship among different pathways of activation. Proc Natl Acad Sci U S A. 1987 Mar;84(6):1654–1658. doi: 10.1073/pnas.84.6.1654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Morley A. A., Trainor K. J., Seshadri R., Ryall R. G. Measurement of in vivo mutations in human lymphocytes. Nature. 1983 Mar 10;302(5904):155–156. doi: 10.1038/302155a0. [DOI] [PubMed] [Google Scholar]
  49. Morley B. J., Chin K. N., Newton M. E., Weiss A. The lysine residue in the membrane-spanning domain of the beta chain is necessary for cell surface expression of the T cell antigen receptor. J Exp Med. 1988 Dec 1;168(6):1971–1978. doi: 10.1084/jem.168.6.1971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Nelson D. L., Biddison W. E., Shaw S. Defective in vitro production of influenza virus-specific cytotoxic T lymphocytes in ataxia-telangiectasia. J Immunol. 1983 Jun;130(6):2629–2634. [PubMed] [Google Scholar]
  51. O'Flynn K., Krensky A. M., Beverley P. C., Burakoff S. J., Linch D. C. Phytohaemagglutinin activation of T cells through the sheep red blood cell receptor. Nature. 1985 Feb 21;313(6004):686–687. doi: 10.1038/313686a0. [DOI] [PubMed] [Google Scholar]
  52. Oettgen H. C., Pettey C. L., Maloy W. L., Terhorst C. A T3-like protein complex associated with the antigen receptor on murine T cells. Nature. 1986 Mar 20;320(6059):272–275. doi: 10.1038/320272a0. [DOI] [PubMed] [Google Scholar]
  53. Ohashi P. S., Mak T. W., Van den Elsen P., Yanagi Y., Yoshikai Y., Calman A. F., Terhorst C., Stobo J. D., Weiss A. Reconstitution of an active surface T3/T-cell antigen receptor by DNA transfer. Nature. 1985 Aug 15;316(6029):606–609. doi: 10.1038/316606a0. [DOI] [PubMed] [Google Scholar]
  54. PETERSON R. D., KELLY W. D., GOOD R. A. ATAXIA-TELANGIECTASIA. ITS ASSOCIATION WITH A DEFECTIVE THYMUS, IMMUNOLOGICAL-DEFICIENCY DISEASE, AND MALIGNANCY. Lancet. 1964 May 30;1(7344):1189–1193. doi: 10.1016/s0140-6736(64)91209-7. [DOI] [PubMed] [Google Scholar]
  55. Russo G., Isobe M., Pegoraro L., Finan J., Nowell P. C., Croce C. M. Molecular analysis of a t(7;14)(q35;q32) chromosome translocation in a T cell leukemia of a patient with ataxia telangiectasia. Cell. 1988 Apr 8;53(1):137–144. doi: 10.1016/0092-8674(88)90495-3. [DOI] [PubMed] [Google Scholar]
  56. Saito T., Weiss A., Miller J., Norcross M. A., Germain R. N. Specific antigen-Ia activation of transfected human T cells expressing murine Ti alpha beta-human T3 receptor complexes. Nature. 1987 Jan 8;325(7000):125–130. doi: 10.1038/325125a0. [DOI] [PubMed] [Google Scholar]
  57. Siekevitz M., Kocks C., Rajewsky K., Dildrop R. Analysis of somatic mutation and class switching in naive and memory B cells generating adoptive primary and secondary responses. Cell. 1987 Mar 13;48(5):757–770. doi: 10.1016/0092-8674(87)90073-0. [DOI] [PubMed] [Google Scholar]
  58. 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]
  59. Taylor A. M., Harnden D. G., Arlett C. F., Harcourt S. A., Lehmann A. R., Stevens S., Bridges B. A. Ataxia telangiectasia: a human mutation with abnormal radiation sensitivity. Nature. 1975 Dec 4;258(5534):427–429. doi: 10.1038/258427a0. [DOI] [PubMed] [Google Scholar]
  60. Uppenkamp M., Pittaluga S., Coupland R., Colamonici O., Cossman J. Stable T3- and T3+ subclones derived from the mosaic human T cell leukemia cell line, CEM. J Immunol. 1988 Apr 15;140(8):2802–2807. [PubMed] [Google Scholar]
  61. Wabl M., Burrows P. D., von Gabain A., Steinberg C. Hypermutation at the immunoglobulin heavy chain locus in a pre-B-cell line. Proc Natl Acad Sci U S A. 1985 Jan;82(2):479–482. doi: 10.1073/pnas.82.2.479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Waldmann T. A., Broder S., Goldman C. K., Frost K., Korsmeyer S. J., Medici M. A. Disorders of B cells and helper T cells in the pathogenesis of the immunoglobulin deficiency of patients with ataxia telangiectasia. J Clin Invest. 1983 Feb;71(2):282–295. doi: 10.1172/JCI110768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Weiss A., Imboden J., Shoback D., Stobo J. Role of T3 surface molecules in human T-cell activation: T3-dependent activation results in an increase in cytoplasmic free calcium. Proc Natl Acad Sci U S A. 1984 Jul;81(13):4169–4173. doi: 10.1073/pnas.81.13.4169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Weiss A., Shields R., Newton M., Manger B., Imboden J. Ligand-receptor interactions required for commitment to the activation of the interleukin 2 gene. J Immunol. 1987 Apr 1;138(7):2169–2176. [PubMed] [Google Scholar]
  65. Weiss A., Stobo J. D. Requirement for the coexpression of T3 and the T cell antigen receptor on a malignant human T cell line. J Exp Med. 1984 Nov 1;160(5):1284–1299. doi: 10.1084/jem.160.5.1284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Wysocki L., Manser T., Gefter M. L. Somatic evolution of variable region structures during an immune response. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1847–1851. doi: 10.1073/pnas.83.6.1847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Yanagi Y., Yoshikai Y., Leggett K., Clark S. P., Aleksander I., Mak T. W. A human T cell-specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains. Nature. 1984 Mar 8;308(5955):145–149. doi: 10.1038/308145a0. [DOI] [PubMed] [Google Scholar]

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

RESOURCES