Abstract
Autoreactive alpha beta T cells have been implicated as playing a primary pathogenic role in a group of diseases characterized by chronic muscle inflammation known as the idiopathic inflammatory myopathies (IIM). gamma delta T cells, a distinct and enigmatic class of T cells, play a less certain role in a variety of human autoimmune diseases including the IIM. In an attempt to understand the significance of gamma delta T cells in the IIM, we utilized a sensitive polymerase chain reaction (PCR) technique to evaluate gamma delta T cell receptor (TCR) gene expression in 45 muscle biopsies obtained from 42 IIM patients (17 polymyositis, 12 dermatomyositis, and 13 inclusion body myositis). gamma delta TCR gene expression was not detected in 36 specimens, the majority of muscle biopsies surveyed. gamma delta TCR gene expression by muscle-infiltrating lymphocytes was detected among nine clinically heterogeneous patients. We further analysed the junctional sequence composition of the V gamma 3 and V delta 1 transcripts, whose expression was prominent among gamma delta positive patients. DNA sequence analysis of V gamma 3 amplification products from two patients revealed the presence of several productively rearranged transcripts with amino acid sequence similarities within the V gamma 3-N-J gamma junctional domain. No amino acid sequence similarities were evident within the V delta-N-D delta-N-J delta region of V delta 1 transcripts amplified from four patients, although a distinct and dominant clonotype was detected from each patient. Our cumulative data suggest that unlike alpha beta T cells, gamma delta T cells do not play a prominent pathologic role in the IIM. In fact, the sporadic nature of gamma delta TCR gene expression detected among these patients implies that gamma delta T cell infiltration, when it occurs, is a secondary event perhaps resulting from non-specific inflammatory processes.
Full text
PDFImages in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Alexandre D., Lefranc M. P. The human gamma/delta + and alpha/beta + T cells: a branched pathway of differentiation. Mol Immunol. 1992 Apr;29(4):447–451. doi: 10.1016/0161-5890(92)90001-e. [DOI] [PubMed] [Google Scholar]
- Beldjord K., Beldjord C., Macintyre E., Even P., Sigaux F. Peripheral selection of V delta 1+ cells with restricted T cell receptor delta gene junctional repertoire in the peripheral blood of healthy donors. J Exp Med. 1993 Jul 1;178(1):121–127. doi: 10.1084/jem.178.1.121. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bohan A., Peter J. B. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975 Feb 13;292(7):344–347. doi: 10.1056/NEJM197502132920706. [DOI] [PubMed] [Google Scholar]
- Bucht A., Söderström K., Hultman T., Uhlén M., Nilsson E., Kiessling R., Grönberg A. T cell receptor diversity and activation markers in the V delta 1 subset of rheumatoid synovial fluid and peripheral blood T lymphocytes. Eur J Immunol. 1992 Feb;22(2):567–574. doi: 10.1002/eji.1830220240. [DOI] [PubMed] [Google Scholar]
- Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
- Dalakas M. C. Polymyositis, dermatomyositis and inclusion-body myositis. N Engl J Med. 1991 Nov 21;325(21):1487–1498. doi: 10.1056/NEJM199111213252107. [DOI] [PubMed] [Google Scholar]
- 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]
- De Libero G., Casorati G., Giachino C., Carbonara C., Migone N., Matzinger P., Lanzavecchia A. Selection by two powerful antigens may account for the presence of the major population of human peripheral gamma/delta T cells. J Exp Med. 1991 Jun 1;173(6):1311–1322. doi: 10.1084/jem.173.6.1311. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Doherty P. J., Yang S. X., Laxer R. M., Silverman E. D., Inman R., Pan S. Evidence for clonal expansion of T cell receptor V gamma II+ T cells in the synovial fluid of patients with arthritis. J Immunol. 1992 Jul 1;149(1):295–299. [PubMed] [Google Scholar]
- Engel A. G., Arahata K., Emslie-Smith A. Immune effector mechanisms in inflammatory myopathies. Res Publ Assoc Res Nerv Ment Dis. 1990;68:141–157. [PubMed] [Google Scholar]
- Forrester J. M., Newman L. S., Wang Y., King T. E., Jr, Kotzin B. L. Clonal expansion of lung V delta 1+ T cells in pulmonary sarcoidosis. J Clin Invest. 1993 Jan;91(1):292–300. doi: 10.1172/JCI116184. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haas W., Pereira P., Tonegawa S. Gamma/delta cells. Annu Rev Immunol. 1993;11:637–685. doi: 10.1146/annurev.iy.11.040193.003225. [DOI] [PubMed] [Google Scholar]
- Hochstenbach F., Brenner M. B. Newly identified gamma delta and beta delta T-cell receptors. J Clin Immunol. 1990 Jan;10(1):1–18. doi: 10.1007/BF00917493. [DOI] [PubMed] [Google Scholar]
- Hohlfeld R., Engel A. G. Expression of 65-kd heat shock proteins in the inflammatory myopathies. Ann Neurol. 1992 Dec;32(6):821–823. doi: 10.1002/ana.410320619. [DOI] [PubMed] [Google Scholar]
- Hohlfeld R., Engel A. G., Ii K., Harper M. C. Polymyositis mediated by T lymphocytes that express the gamma/delta receptor. N Engl J Med. 1991 Mar 28;324(13):877–881. doi: 10.1056/NEJM199103283241303. [DOI] [PubMed] [Google Scholar]
- Hohlfeld R., Engel A. G. The role of gamma-delta T lymphocytes in inflammatory muscle disease. Chem Immunol. 1992;53:75–85. [PubMed] [Google Scholar]
- Hohlfeld R., Goebels N., Engel A. G. Cellular mechanisms in inflammatory myopathies. Baillieres Clin Neurol. 1993 Nov;2(3):617–635. [PubMed] [Google Scholar]
- Hvas J., Oksenberg J. R., Fernando R., Steinman L., Bernard C. C. Gamma delta T cell receptor repertoire in brain lesions of patients with multiple sclerosis. J Neuroimmunol. 1993 Jul;46(1-2):225–234. doi: 10.1016/0165-5728(93)90253-u. [DOI] [PubMed] [Google Scholar]
- Kabelitz D. Human gamma delta T lymphocytes. Int Arch Allergy Immunol. 1993;102(1):1–9. doi: 10.1159/000236544. [DOI] [PubMed] [Google Scholar]
- Kageyama Y., Koide Y., Miyamoto S., Inoue T., Yoshida T. O. The biased V gamma gene usage in the synovial fluid of patients with rheumatoid arthritis. Eur J Immunol. 1994 May;24(5):1122–1129. doi: 10.1002/eji.1830240517. [DOI] [PubMed] [Google Scholar]
- Kalovidouris A. E. Immune aspects of myositis. Curr Opin Rheumatol. 1992 Dec;4(6):809–814. [PubMed] [Google Scholar]
- Kohsaka H., Chen P. P., Taniguchi A., Ollier W. E., Carson D. A. Regulation of the mature human T cell receptor gamma repertoire by biased V-J gene rearrangement. J Clin Invest. 1993 Jan;91(1):171–178. doi: 10.1172/JCI116167. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Leff R. L., Burgess S. H., Miller F. W., Love L. A., Targoff I. N., Dalakas M. C., Joffe M. M., Plotz P. H. Distinct seasonal patterns in the onset of adult idiopathic inflammatory myopathy in patients with anti-Jo-1 and anti-signal recognition particle autoantibodies. Arthritis Rheum. 1991 Nov;34(11):1391–1396. doi: 10.1002/art.1780341108. [DOI] [PubMed] [Google Scholar]
- Love L. A., Leff R. L., Fraser D. D., Targoff I. N., Dalakas M., Plotz P. H., Miller F. W. A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups. Medicine (Baltimore) 1991 Nov;70(6):360–374. doi: 10.1097/00005792-199111000-00002. [DOI] [PubMed] [Google Scholar]
- Mantegazza R., Andreetta F., Bernasconi P., Baggi F., Oksenberg J. R., Simoncini O., Mora M., Cornelio F., Steinman L. Analysis of T cell receptor repertoire of muscle-infiltrating T lymphocytes in polymyositis. Restricted V alpha/beta rearrangements may indicate antigen-driven selection. J Clin Invest. 1993 Jun;91(6):2880–2886. doi: 10.1172/JCI116533. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McIntosh R. S., Tandon N., Pickerill A. P., Davies R., Barnett D., Weetman A. P. The gamma delta T cell repertoire in Graves' disease and multinodular goitre. Clin Exp Immunol. 1993 Dec;94(3):473–477. doi: 10.1111/j.1365-2249.1993.tb08220.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miller F. W. Humoral immunity and immunogenetics in the idiopathic inflammatory myopathies. Curr Opin Rheumatol. 1991 Dec;3(6):902–910. doi: 10.1097/00002281-199112000-00002. [DOI] [PubMed] [Google Scholar]
- Miller F. W. Myositis-specific autoantibodies. Touchstones for understanding the inflammatory myopathies. JAMA. 1993 Oct 20;270(15):1846–1849. doi: 10.1001/jama.270.15.1846. [DOI] [PubMed] [Google Scholar]
- Miller F. W., Twitty S. A., Biswas T., Plotz P. H. Origin and regulation of a disease-specific autoantibody response. Antigenic epitopes, spectrotype stability, and isotype restriction of anti-Jo-1 autoantibodies. J Clin Invest. 1990 Feb;85(2):468–475. doi: 10.1172/JCI114461. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moss P. A., Rosenberg W. M., Bell J. I. The human T cell receptor in health and disease. Annu Rev Immunol. 1992;10:71–96. doi: 10.1146/annurev.iy.10.040192.000443. [DOI] [PubMed] [Google Scholar]
- O'Hanlon T. P., Dalakas M. C., Plotz P. H., Miller F. W. Predominant TCR-alpha beta variable and joining gene expression by muscle-infiltrating lymphocytes in the idiopathic inflammatory myopathies. J Immunol. 1994 Mar 1;152(5):2569–2576. [PubMed] [Google Scholar]
- O'Hanlon T. P., Dalakas M. C., Plotz P. H., Miller F. W. The alpha beta T-cell receptor repertoire in inclusion body myositis: diverse patterns of gene expression by muscle-infiltrating lymphocytes. J Autoimmun. 1994 Jun;7(3):321–333. doi: 10.1006/jaut.1994.1023. [DOI] [PubMed] [Google Scholar]
- Ohta M., Sato N. The cytotoxic analysis of T cell receptor V delta 1+ T cell lines derived from the synovial fluid of rheumatoid arthritis patients. Clin Exp Immunol. 1994 Aug;97(2):193–199. doi: 10.1111/j.1365-2249.1994.tb06067.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Oksenberg J. R., Panzara M. A., Begovich A. B., Mitchell D., Erlich H. A., Murray R. S., Shimonkevitz R., Sherritt M., Rothbard J., Bernard C. C. Selection for T-cell receptor V beta-D beta-J beta gene rearrangements with specificity for a myelin basic protein peptide in brain lesions of multiple sclerosis. Nature. 1993 Mar 4;362(6415):68–70. doi: 10.1038/362068a0. [DOI] [PubMed] [Google Scholar]
- Olive C., Gatenby P. A., Serjeantson S. W. Evidence for oligoclonality of T cell receptor delta chain transcripts expressed in rheumatoid arthritis patients. Eur J Immunol. 1992 Oct;22(10):2587–2593. doi: 10.1002/eji.1830221018. [DOI] [PubMed] [Google Scholar]
- Olive C., Gatenby P. A., Serjeantson S. W. Molecular characterization of the V gamma 9 T cell receptor repertoire expressed in patients with rheumatoid arthritis. Eur J Immunol. 1992 Nov;22(11):2901–2906. doi: 10.1002/eji.1830221122. [DOI] [PubMed] [Google Scholar]
- Olive C., Gatenby P. A., Serjeantson S. W. Variable gene usage of T cell receptor gamma- and delta-chain transcripts expressed in synovia and peripheral blood of patients with rheumatoid arthritis. Clin Exp Immunol. 1992 Feb;87(2):172–177. doi: 10.1111/j.1365-2249.1992.tb02970.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Paliard X., West S. G., Lafferty J. A., Clements J. R., Kappler J. W., Marrack P., Kotzin B. L. Evidence for the effects of a superantigen in rheumatoid arthritis. Science. 1991 Jul 19;253(5017):325–329. doi: 10.1126/science.1857971. [DOI] [PubMed] [Google Scholar]
- Plotz P. H., Dalakas M., Leff R. L., Love L. A., Miller F. W., Cronin M. E. Current concepts in the idiopathic inflammatory myopathies: polymyositis, dermatomyositis, and related disorders. Ann Intern Med. 1989 Jul 15;111(2):143–157. doi: 10.7326/0003-4819-111-2-143. [DOI] [PubMed] [Google Scholar]
- Pluschke G., Rüegg D., Hohlfeld R., Engel A. G. Autoaggressive myocytotoxic T lymphocytes expressing an unusual gamma/delta T cell receptor. J Exp Med. 1992 Dec 1;176(6):1785–1789. doi: 10.1084/jem.176.6.1785. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Porcelli S., Brenner M. B., Band H. Biology of the human gamma delta T-cell receptor. Immunol Rev. 1991 Apr;120:137–183. doi: 10.1111/j.1600-065x.1991.tb00591.x. [DOI] [PubMed] [Google Scholar]
- Quertermous T., Strauss W., Murre C., Dialynas D. P., Strominger J. L., Seidman J. G. Human T-cell gamma genes contain N segments and have marked junctional variability. Nature. 1986 Jul 10;322(6075):184–187. doi: 10.1038/322184a0. [DOI] [PubMed] [Google Scholar]
- Rock E. P., Sibbald P. R., Davis M. M., Chien Y. H. CDR3 length in antigen-specific immune receptors. J Exp Med. 1994 Jan 1;179(1):323–328. doi: 10.1084/jem.179.1.323. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Roura-Mir I. C., Alcalde L., Vargas F., Tolosa E., Obiols G., Foz M., Jaraquemada D., Pujol-Borrell R. Gamma delta lymphocytes in endocrine autoimmunity: evidence of expansion in Graves' disease but not in type 1 diabetes. Clin Exp Immunol. 1993 May;92(2):288–295. doi: 10.1111/j.1365-2249.1993.tb03394.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schild H., Mavaddat N., Litzenberger C., Ehrich E. W., Davis M. M., Bluestone J. A., Matis L., Draper R. K., Chien Y. H. The nature of major histocompatibility complex recognition by gamma delta T cells. Cell. 1994 Jan 14;76(1):29–37. doi: 10.1016/0092-8674(94)90170-8. [DOI] [PubMed] [Google Scholar]
- Schondelmaier S., Wesch D., Pechhold K., Kabelitz D. V gamma gene usage in peripheral blood gamma delta T cells. Immunol Lett. 1993 Oct;38(2):121–126. doi: 10.1016/0165-2478(93)90176-3. [DOI] [PubMed] [Google Scholar]
- Selmaj K., Brosnan C. F., Raine C. S. Colocalization of lymphocytes bearing gamma delta T-cell receptor and heat shock protein hsp65+ oligodendrocytes in multiple sclerosis. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6452–6456. doi: 10.1073/pnas.88.15.6452. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shimonkevitz R., Colburn C., Burnham J. A., Murray R. S., Kotzin B. L. Clonal expansions of activated gamma/delta T cells in recent-onset multiple sclerosis. Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):923–927. doi: 10.1073/pnas.90.3.923. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sinha A. A., Lopez M. T., McDevitt H. O. Autoimmune diseases: the failure of self tolerance. Science. 1990 Jun 15;248(4961):1380–1388. doi: 10.1126/science.1972595. [DOI] [PubMed] [Google Scholar]
- Strauss W. M., Quertermous T., Seidman J. G. Measuring the human T cell receptor gamma-chain locus. Science. 1987 Sep 4;237(4819):1217–1219. doi: 10.1126/science.3498213. [DOI] [PubMed] [Google Scholar]
- Takeshita S., Toda M., Yamagishi H. Excision products of the T cell receptor gene support a progressive rearrangement model of the alpha/delta locus. EMBO J. 1989 Nov;8(11):3261–3270. doi: 10.1002/j.1460-2075.1989.tb08486.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takihara Y., Reimann J., Michalopoulos E., Ciccone E., Moretta L., Mak T. W. Diversity and structure of human T cell receptor delta chain genes in peripheral blood gamma/delta-bearing T lymphocytes. J Exp Med. 1989 Feb 1;169(2):393–405. doi: 10.1084/jem.169.2.393. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tsuruta Y., Yoshioka T., Suzuki R., Sakata T. Analysis of the population of human T cell receptor gamma and delta chain variable region subfamilies by reverse dot blot hybridization. J Immunol Methods. 1994 Feb 28;169(1):17–23. doi: 10.1016/0022-1759(94)90120-1. [DOI] [PubMed] [Google Scholar]
- Uyemura K., Deans R. J., Band H., Ohmen J., Panchamoorthy G., Morita C. T., Rea T. H., Modlin R. L. Evidence for clonal selection of gamma/delta T cells in response to a human pathogen. J Exp Med. 1991 Sep 1;174(3):683–692. doi: 10.1084/jem.174.3.683. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Uyemura K., Klotz J., Pirmez C., Ohmen J., Wang X. H., Ho C., Hoffman W. L., Modlin R. L. Microanatomic clonality of gamma delta T cells in human leishmaniasis lesions. J Immunol. 1992 Feb 15;148(4):1205–1211. [PubMed] [Google Scholar]
- Wucherpfennig K. W., Newcombe J., Li H., Keddy C., Cuzner M. L., Hafler D. A. Gamma delta T-cell receptor repertoire in acute multiple sclerosis lesions. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4588–4592. doi: 10.1073/pnas.89.10.4588. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yurovsky V. V., Sutton P. A., Schulze D. H., Wigley F. M., Wise R. A., Howard R. F., White B. Expansion of selected V delta 1+ gamma delta T cells in systemic sclerosis patients. J Immunol. 1994 Jul 15;153(2):881–891. [PubMed] [Google Scholar]