Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1988 Oct;82(4):1183–1191. doi: 10.1172/JCI113715

Bias toward use of a specific T cell receptor beta-chain variable region in a subgroup of individuals with sarcoidosis.

D R Moller 1, K Konishi 1, M Kirby 1, B Balbi 1, R G Crystal 1
PMCID: PMC442668  PMID: 2459159

Abstract

To evaluate the concept that biases in the usage of T cell antigen receptor beta variable (V) regions may be manifested in T lymphocytes that accumulate in nonmalignant, T cell-mediated human disorders, a V beta 8-specific antibody (anti-Ti3A, 5REX9H5) was used to evaluate lung and blood T cells in pulmonary sarcoidosis, a chronic granulomatous disorder of unknown etiology. Whereas normal patients had less than 5% Ti3A+ lung (n = 7) and/or blood (n = 9) lymphocytes, strikingly, a subgroup (8 of 21) with active pulmonary sarcoidosis had greater than 7% Ti3A+ lung and/or blood T cells and a higher proportion of Ti3A+ lymphocytes in the lung compared with blood. Dual-color flow cytometry demonstrated compartmentalization of Ti3A+ CD4+ lymphocytes to lung and Ti3A+ CD8+ lymphocytes to blood. Analysis with a 32P-labeled V beta 8 probe revealed that sarcoid lung T lymphocytes contained higher amounts of V beta 8+ mRNA than autologous blood T cells. However, Southern analysis of sarcoid lung and blood T cell DNA demonstrated no evidence of clonal rearrangements of V beta 8 genes. These observations demonstrate a clear bias toward the use of at least one V beta region in sarcoidosis, and suggests T cells accumulate secondary to external selective pressure, rather than in a random polyclonal fashion or by clonal expansion of one or few T cell clones.

Full text

PDF
1183

Images in this article

Selected References

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

  1. Acuto O., Campen T. J., Royer H. D., Hussey R. E., Poole C. B., Reinherz E. L. Molecular analysis of T cell receptor (Ti) variable region (V) gene expression. Evidence that a single Ti beta V gene family can be used in formation of V domains on phenotypically and functionally diverse T cell populations. J Exp Med. 1985 Jun 1;161(6):1326–1343. doi: 10.1084/jem.161.6.1326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  3. Acuto O., Hussey R. E., Reinherz E. L. Multiple class I and class II major histocompatibility complex allospecificities are generated with T cell receptor variable (V) domains created by a single Ti beta V gene family. J Exp Med. 1985 Oct 1;162(4):1387–1392. doi: 10.1084/jem.162.4.1387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barth R. K., Kim B. S., Lan N. C., Hunkapiller T., Sobieck N., Winoto A., Gershenfeld H., Okada C., Hansburg D., Weissman I. L. The murine T-cell receptor uses a limited repertoire of expressed V beta gene segments. Nature. 1985 Aug 8;316(6028):517–523. doi: 10.1038/316517a0. [DOI] [PubMed] [Google Scholar]
  5. Bauer W., Gorny M. K., Baumann H. R., Morell A. T-lymphocyte subsets and immunoglobulin concentrations in bronchoalveolar lavage of patients with sarcoidosis and high and low intensity alveolitis. Am Rev Respir Dis. 1985 Nov;132(5):1060–1065. doi: 10.1164/arrd.1985.132.5.1060. [DOI] [PubMed] [Google Scholar]
  6. Boylston A. W., Borst J., Yssel H., Blanchard D., Spits H., de Vries J. E. Properties of a panel of monoclonal antibodies which react with the human T cell antigen receptor on the leukemic line HPB-ALL and a subset of normal peripheral blood T lymphocytes. J Immunol. 1986 Jul 15;137(2):741–744. [PubMed] [Google Scholar]
  7. Budd R. C., Miescher G. C., Howe R. C., Lees R. K., Bron C., MacDonald H. R. Developmentally regulated expression of T cell receptor beta chain variable domains in immature thymocytes. J Exp Med. 1987 Aug 1;166(2):577–582. doi: 10.1084/jem.166.2.577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. 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]
  9. Concannon P., Gatti R. A., Hood L. E. Human T cell receptor V beta gene polymorphism. J Exp Med. 1987 Apr 1;165(4):1130–1140. doi: 10.1084/jem.165.4.1130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Concannon P., Lai E., Klein M., Siu S., Strauss E., Pickering L., Kung P., Gatti R., Hood L. Human T-cell receptor genes: organization, diversity, and polymorphism. Cold Spring Harb Symp Quant Biol. 1986;51(Pt 2):785–789. doi: 10.1101/sqb.1986.051.01.091. [DOI] [PubMed] [Google Scholar]
  11. Concannon P., Pickering L. A., Kung P., Hood L. Diversity and structure of human T-cell receptor beta-chain variable region genes. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6598–6602. doi: 10.1073/pnas.83.17.6598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Daniele R. P., Dauber J. H., Rossman M. D. Immunologic abnormalities in sarcoidosis. Ann Intern Med. 1980 Mar;92(3):406–416. doi: 10.7326/0003-4819-92-3-406. [DOI] [PubMed] [Google Scholar]
  13. Dembić Z., Haas W., Weiss S., McCubrey J., Kiefer H., von Boehmer H., Steinmetz M. Transfer of specificity by murine alpha and beta T-cell receptor genes. Nature. 1986 Mar 20;320(6059):232–238. doi: 10.1038/320232a0. [DOI] [PubMed] [Google Scholar]
  14. Epstein P. E., Dauber J. H., Rossman M. D., Daniele R. P. Bronchoalveolar lavage in a patient with chronic berylliosis: evidence for hypersensitivity pneumonitis. Ann Intern Med. 1982 Aug;97(2):213–216. doi: 10.7326/0003-4819-97-2-213. [DOI] [PubMed] [Google Scholar]
  15. Fink P. J., Matis L. A., McElligott D. L., Bookman M., Hedrick S. M. Correlations between T-cell specificity and the structure of the antigen receptor. Nature. 1986 May 15;321(6067):219–226. doi: 10.1038/321219a0. [DOI] [PubMed] [Google Scholar]
  16. Fowlkes B. J., Kruisbeek A. M., Ton-That H., Weston M. A., Coligan J. E., Schwartz R. H., Pardoll D. M. A novel population of T-cell receptor alpha beta-bearing thymocytes which predominantly expresses a single V beta gene family. Nature. 1987 Sep 17;329(6136):251–254. doi: 10.1038/329251a0. [DOI] [PubMed] [Google Scholar]
  17. Garman R. D., Ko J. L., Vulpe C. D., Raulet D. H. T-cell receptor variable region gene usage in T-cell populations. Proc Natl Acad Sci U S A. 1986 Jun;83(11):3987–3991. doi: 10.1073/pnas.83.11.3987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gillis S., Watson J. Biochemical and biological characterization of lymphocyte regulatory molecules. V. Identification of an interleukin 2-producing human leukemia T cell line. J Exp Med. 1980 Dec 1;152(6):1709–1719. doi: 10.1084/jem.152.6.1709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Goverman J., Minard K., Shastri N., Hunkapiller T., Hansburg D., Sercarz E., Hood L. Rearranged beta T cell receptor genes in a helper T cell clone specific for lysozyme: no correlation between V beta and MHC restriction. Cell. 1985 Apr;40(4):859–867. doi: 10.1016/0092-8674(85)90345-9. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Hedrick S. M., Cohen D. I., Nielsen E. A., Davis M. M. Isolation of cDNA clones encoding T cell-specific membrane-associated proteins. Nature. 1984 Mar 8;308(5955):149–153. doi: 10.1038/308149a0. [DOI] [PubMed] [Google Scholar]
  22. Hochgeschwender U., Simon H. G., Weltzien H. U., Bartels F., Becker A., Epplen J. T. Dominance of one T-cell receptor in the H-2Kb/TNP response. Nature. 1987 Mar 19;326(6110):307–309. doi: 10.1038/326307a0. [DOI] [PubMed] [Google Scholar]
  23. Hunninghake G. W., Bedell G. N., Zavala D. C., Monick M., Brady M. Role of interleukin-2 release by lung T-cells in active pulmonary sarcoidosis. Am Rev Respir Dis. 1983 Oct;128(4):634–638. doi: 10.1164/arrd.1983.128.4.634. [DOI] [PubMed] [Google Scholar]
  24. Hunninghake G. W., Crystal R. G. Pulmonary sarcoidosis: a disorder mediated by excess helper T-lymphocyte activity at sites of disease activity. N Engl J Med. 1981 Aug 20;305(8):429–434. doi: 10.1056/NEJM198108203050804. [DOI] [PubMed] [Google Scholar]
  25. Jerne N. K. The somatic generation of immune recognition. Eur J Immunol. 1971 Jan;1(1):1–9. doi: 10.1002/eji.1830010102. [DOI] [PubMed] [Google Scholar]
  26. Kappler J. W., Wade T., White J., Kushnir E., Blackman M., Bill J., Roehm N., Marrack P. A T cell receptor V beta segment that imparts reactivity to a class II major histocompatibility complex product. Cell. 1987 Apr 24;49(2):263–271. doi: 10.1016/0092-8674(87)90567-8. [DOI] [PubMed] [Google Scholar]
  27. Keogh B. A., Hunninghake G. W., Line B. R., Crystal R. G. The alveolitis of pulmonary sarcoidosis. Evaluation of natural history and alveolitis-dependent changes in lung function. Am Rev Respir Dis. 1983 Aug;128(2):256–265. doi: 10.1164/arrd.1983.128.2.256. [DOI] [PubMed] [Google Scholar]
  28. Kimura N., Toyonaga B., Yoshikai Y., Du R. P., Mak T. W. Sequences and repertoire of the human T cell receptor alpha and beta chain variable region genes in thymocytes. Eur J Immunol. 1987 Mar;17(3):375–383. doi: 10.1002/eji.1830170312. [DOI] [PubMed] [Google Scholar]
  29. Kimura N., Toyonaga B., Yoshikai Y., Triebel F., Debre P., Minden M. D., Mak T. W. Sequences and diversity of human T cell receptor beta chain variable region genes. J Exp Med. 1986 Sep 1;164(3):739–750. doi: 10.1084/jem.164.3.739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Konishi K., Moller D. R., Saltini C., Kirby M., Crystal R. G. Spontaneous expression of the interleukin 2 receptor gene and presence of functional interleukin 2 receptors on T lymphocytes in the blood of individuals with active pulmonary sarcoidosis. J Clin Invest. 1988 Sep;82(3):775–781. doi: 10.1172/JCI113678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. MacDonald H. R., Lees R. K., Bron C., Sordat B., Miescher G. T cell antigen receptor expression in athymic (nu/nu) mice. Evidence for an oligoclonal beta chain repertoire. J Exp Med. 1987 Jul 1;166(1):195–209. doi: 10.1084/jem.166.1.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. 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]
  33. Modlin R. L., Hofman F. M., Meyer P. R., Sharma O. P., Taylor C. R., Rea T. H. In situ demonstration of T lymphocyte subsets in granulomatous inflammation: leprosy, rhinoscleroma and sarcoidosis. Clin Exp Immunol. 1983 Mar;51(3):430–438. [PMC free article] [PubMed] [Google Scholar]
  34. Morel P. A., Livingstone A. M., Fathman C. G. Correlation of T cell receptor V beta gene family with MHC restriction. J Exp Med. 1987 Aug 1;166(2):583–588. doi: 10.1084/jem.166.2.583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Müller-Quernheim J., Saltini C., Sondermeyer P., Crystal R. G. Compartmentalized activation of the interleukin 2 gene by lung T lymphocytes in active pulmonary sarcoidosis. J Immunol. 1986 Dec 1;137(11):3475–3483. [PubMed] [Google Scholar]
  36. Pardoll D. M., Fowlkes B. J., Lechler R. I., Germain R. N., Schwartz R. H. Early genetic events in T cell development analyzed by in situ hybridization. J Exp Med. 1987 Jun 1;165(6):1624–1638. doi: 10.1084/jem.165.6.1624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Pinkston P., Bitterman P. B., Crystal R. G. Spontaneous release of interleukin-2 by lung T lymphocytes in active pulmonary sarcoidosis. N Engl J Med. 1983 Apr 7;308(14):793–800. doi: 10.1056/NEJM198304073081401. [DOI] [PubMed] [Google Scholar]
  38. Reynolds H. Y., Fulmer J. D., Kazmierowski J. A., Roberts W. C., Frank M. M., Crystal R. G. Analysis of cellular and protein content of broncho-alveolar lavage fluid from patients with idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis. J Clin Invest. 1977 Jan;59(1):165–175. doi: 10.1172/JCI108615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Rossi G. A., Sacco O., Cosulich E., Risso A., Balbi B., Ravazzoni C. Helper T-lymphocytes in pulmonary sarcoidosis. Functional analysis of a lung T-cell subpopulation in patients with active disease. Am Rev Respir Dis. 1986 Jun;133(6):1086–1090. doi: 10.1164/arrd.1986.133.6.1086. [DOI] [PubMed] [Google Scholar]
  40. Royer H. D., Bensussan A., Acuto O., Reinherz E. L. Functional isotypes are not encoded by the constant region genes of the beta subunit of the T cell receptor for antigen/major histocompatibility complex. J Exp Med. 1984 Sep 1;160(3):947–952. doi: 10.1084/jem.160.3.947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Rupp F., Acha-Orbea H., Hengartner H., Zinkernagel R., Joho R. Identical V beta T-cell receptor genes used in alloreactive cytotoxic and antigen plus I-A specific helper T cells. 1985 May 30-Jun 5Nature. 315(6018):425–427. doi: 10.1038/315425a0. [DOI] [PubMed] [Google Scholar]
  42. Rupp F., Brecher J., Giedlin M. A., Mosmann T., Zinkernagel R. M., Hengartner H., Joho R. H. T-cell antigen receptors with identical variable regions but different diversity and joining region gene segments have distinct specificities but cross-reactive idiotypes. Proc Natl Acad Sci U S A. 1987 Jan;84(1):219–222. doi: 10.1073/pnas.84.1.219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Saito T., Germain R. N. Predictable acquisition of a new MHC recognition specificity following expression of a transfected T-cell receptor beta-chain gene. Nature. 1987 Sep 17;329(6136):256–259. doi: 10.1038/329256a0. [DOI] [PubMed] [Google Scholar]
  44. Saltini C., Hance A. J., Ferrans V. J., Basset F., Bitterman P. B., Crystal R. G. Accurate quantification of cells recovered by bronchoalveolar lavage. Am Rev Respir Dis. 1984 Oct;130(4):650–658. doi: 10.1164/arrd.1984.130.4.650. [DOI] [PubMed] [Google Scholar]
  45. Saltini C., Spurzem J. R., Lee J. J., Pinkston P., Crystal R. G. Spontaneous release of interleukin 2 by lung T lymphocytes in active pulmonary sarcoidosis is primarily from the Leu3+DR+ T cell subset. J Clin Invest. 1986 Jun;77(6):1962–1970. doi: 10.1172/JCI112525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Semenzato G., Agostini C., Trentin L., Zambello R., Chilosi M., Cipriani A., Ossi E., Angi M. R., Morittu L., Pizzolo G. Evidence of cells bearing interleukin-2 receptor at sites of disease activity in sarcoid patients. Clin Exp Immunol. 1984 Aug;57(2):331–337. [PMC free article] [PubMed] [Google Scholar]
  47. Siliciano R. F., Hemesath T. J., Pratt J. C., Dintzis R. Z., Dintzis H. M., Acuto O., Shin H. S., Reinherz E. L. Direct evidence for the existence of nominal antigen binding sites on T cell surface Ti alpha-beta heterodimers of MHC-restricted T cell clones. Cell. 1986 Oct 24;47(2):161–171. doi: 10.1016/0092-8674(86)90439-3. [DOI] [PubMed] [Google Scholar]
  48. Singer P. A., McEvilly R. J., Noonan D. J., Dixon F. J., Theofilopoulos A. N. Clonal diversity and T-cell receptor beta-chain variable gene expression in enlarged lymph nodes of MRL-lpr/lpr lupus mice. Proc Natl Acad Sci U S A. 1986 Sep;83(18):7018–7022. doi: 10.1073/pnas.83.18.7018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Siu G., Clark S. P., Yoshikai Y., Malissen M., Yanagi Y., Strauss E., Mak T. W., Hood L. The human T cell antigen receptor is encoded by variable, diversity, and joining gene segments that rearrange to generate a complete V gene. Cell. 1984 Jun;37(2):393–401. doi: 10.1016/0092-8674(84)90369-6. [DOI] [PubMed] [Google Scholar]
  50. Siu G., Strauss E. C., Lai E., Hood L. E. Analysis of a human V beta gene subfamily. J Exp Med. 1986 Nov 1;164(5):1600–1614. doi: 10.1084/jem.164.5.1600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  52. Sredni B., Schwartz R. H. Alloreactivity of an antigen-specific T-cell clone. Nature. 1980 Oct 30;287(5785):855–857. doi: 10.1038/287855a0. [DOI] [PubMed] [Google Scholar]
  53. Tillinghast J. P., Behlke M. A., Loh D. Y. Structure and diversity of the human T-cell receptor beta-chain variable region genes. Science. 1986 Aug 22;233(4766):879–883. doi: 10.1126/science.3755549. [DOI] [PubMed] [Google Scholar]
  54. Winoto A., Urban J. L., Lan N. C., Goverman J., Hood L., Hansburg D. Predominant use of a V alpha gene segment in mouse T-cell receptors for cytochrome c. Nature. 1986 Dec 18;324(6098):679–682. doi: 10.1038/324679a0. [DOI] [PubMed] [Google Scholar]
  55. Yagüe J., White J., Coleclough C., Kappler J., Palmer E., Marrack P. The T cell receptor: the alpha and beta chains define idiotype, and antigen and MHC specificity. Cell. 1985 Aug;42(1):81–87. doi: 10.1016/s0092-8674(85)80103-3. [DOI] [PubMed] [Google Scholar]
  56. 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]
  57. 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]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES