Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1983 Nov;72(5):1686–1697. doi: 10.1172/JCI111128

Impaired T cell capping and receptor regeneration in active systemic lupus erythematosus. Evidence for a disorder intrinsic to the T lymphocyte.

G M Kammer
PMCID: PMC370457  PMID: 6355184

Abstract

It is currently unclear whether the T cell dysfunctions observed during active systemic lupus erythematosus (SLE) reflect a disorder intrinsic to the T cell or defects that result from interaction with anti-T cell autoantibody. To determine whether a disorder intrinsic to the T cell exists in SLE, the T cell capping mechanism was selected as a model of cellular function. The normal T cell capping mechanism is a rapid, energy-dependent and coordinated sequence of membrane events that consists of microaggregation, capping, endocytosis, and regeneration of the surface molecule. The monoclonal antibodies OKT3, OKT4, and OKT8, directed against the T cell-specific membrane glycoproteins T-3, T-4, T-8, served as specific probes of the glycoproteins' mobility within the membrane and membrane glycoprotein regeneration. When compared with greater than 91% T cell capping in normal and control subjects with active Sjögren's syndrome, active rheumatoid arthritis and active tuberculosis, only 49-60% of T cells from active SLE patients completed the capping sequence (SLE vs. healthy controls; T-3, P less than 0.002; T-4, P less than 0.004; T-8, P less than 0.002). Colchicine (10(-5) M), which inhibits microtuble polymerization and augments the rate of normal T cell capping, failed to restore the abnormal capping. However, as judged by the elapsed time intervals to half-maximal capping, the capping kinetics of the T cells able to initiate capping were not significantly different from controls. Fluorescence microscopy demonstrated an abnormal staining pattern characterized by microaggregation of ligand-glycoprotein complexes on resting T cells, coarse aggregation of ligand-glycoprotein complexes over the surfaces of cells that failed to cap, and cleaved or disrupted caps. After clearance of determinants by capping, greater than 94% of T cells from healthy controls regenerated T-3, -4, and -8 within 24 h. In contrast, only 20-40% of capped T cells from active SLE patients reexpressed new determinants. With improving disease activity, the proportion of cells capping and regenerating T-3, -4, and -8 increased, but remained significantly below control levels. In conclusion, this study has identified a disorder of T cell surface glycoprotein mobility and regeneration affecting the majority (60-80%) of both the T-3+, T-4+, (inducer/helper), and T-3+, T-8+ (suppressor) subsets during active SLE. Although the impaired capping and reexpression improve with disease remission, a residual defect persists. The data support the concept of a disorder intrinsic to the T cell in SLE.

Full text

PDF
1697

Images in this article

1692Image
on p.1692
1693Image
on p.1693

Selected References

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

  1. Alcocer-Varela J., Alarcón-Segovia D. Decreased production of and response to interleukin-2 by cultured lymphocytes from patients with systemic lupus erythematosus. J Clin Invest. 1982 Jun;69(6):1388–1392. doi: 10.1172/JCI110579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ault K. A., Unanue E. R. Failure of B lymphocytes in human blood to regenerate surface immunoglobulin after its removal by antibody. J Immunol. 1977 Jul;119(1):327–329. [PubMed] [Google Scholar]
  3. Birch R. E., Polmar S. H. Pharmacological modification of immunoregulatory T lymphocytes. I. Effect of adenosine, H1 and H2 histamine agonists upon T lymphocyte regulation of B lymphocyte differentiation in vitro. Clin Exp Immunol. 1982 Apr;48(1):218–230. [PMC free article] [PubMed] [Google Scholar]
  4. Birch R. E., Rosenthal A. K., Polmar S. H. Pharmacological modification of immunoregulatory T lymphocytes . II. Modulation of T lymphocyte cell surface characteristics. Clin Exp Immunol. 1982 Apr;48(1):231–238. [PMC free article] [PubMed] [Google Scholar]
  5. Bourguignon L. Y., Singer S. J. Transmembrane interactions and the mechanism of capping of surface receptors by their specific ligands. Proc Natl Acad Sci U S A. 1977 Nov;74(11):5031–5035. doi: 10.1073/pnas.74.11.5031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Butman B. T., Jacobsen T., Cabatu O. G., Bourguignon L. Y. The involvement of cAMP in lymphocyte capping. Cell Immunol. 1981 Jul 1;61(2):397–403. doi: 10.1016/0008-8749(81)90387-7. [DOI] [PubMed] [Google Scholar]
  7. Chang T. W., Kung P. C., Gingras S. P., Goldstein G. Does OKT3 monoclonal antibody react with an antigen-recognition structure on human T cells? Proc Natl Acad Sci U S A. 1981 Mar;78(3):1805–1808. doi: 10.1073/pnas.78.3.1805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Charpentier B., Carnaud C., Bach J. F. Selective depression of the xenogeneic cell-mediated lympholysis in systemic lupus erythematosus. J Clin Invest. 1979 Aug;64(2):351–360. doi: 10.1172/JCI109469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cooper D. A., Petts V., Luckhurst E., Penny R. The effect of acute and prolonged administration of prednisolone and ACTH on lymphocyte subpopulations. Clin Exp Immunol. 1977 Jun;28(3):467–473. [PMC free article] [PubMed] [Google Scholar]
  10. Edelman G. M. Surface modulation in cell recognition and cell growth. Science. 1976 Apr 16;192(4236):218–226. doi: 10.1126/science.769162. [DOI] [PubMed] [Google Scholar]
  11. Edelman G. M., Yahara I., Wang J. L. Receptor mobility and receptor-cytoplasmic interactions in lymphocytes. Proc Natl Acad Sci U S A. 1973 May;70(5):1442–1446. doi: 10.1073/pnas.70.5.1442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fauci A. S., Steinberg A. D., Haynes B. F., Whalen G. Immunoregulatory aberrations in systemic lupus erythematosus. J Immunol. 1978 Oct;121(4):1473–1479. [PubMed] [Google Scholar]
  13. Flanagan J., Koch G. L. Cross-linked surface Ig attaches to actin. Nature. 1978 May 25;273(5660):278–281. doi: 10.1038/273278a0. [DOI] [PubMed] [Google Scholar]
  14. Gladman D., Keystone E., Urowitz M., Cane D., Poplonski L. Impaired antigen-specific suppressor cell activity in patients with systemic lupus erythematosus. Clin Exp Immunol. 1980 Apr;40(1):77–82. [PMC free article] [PubMed] [Google Scholar]
  15. Gottlieb A. B., Lahita R. G., Chiorazzi N., Kunkel H. G. Immune function in systemic lupus erythematosus. Impairment of in vitro T-cell proliferation and in vivo antibody response to exogenous antigen. J Clin Invest. 1979 May;63(5):885–892. doi: 10.1172/JCI109388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hafeman D. G., Smith L. M., Fearon D. T., McConnell H. M. Lipid monolayer-coated solid surfaces do not perturb the lateral motion and distribution of C3b receptors on neutrophils. J Cell Biol. 1982 Jul;94(1):224–227. doi: 10.1083/jcb.94.1.224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Haynes B. F., Fauci A. S. The differential effect of in vivo hydrocortisone on the kinetics of subpopulations of human peripheral blood thymus-derived lymphocytes. J Clin Invest. 1978 Mar;61(3):703–707. doi: 10.1172/JCI108982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Henis Y. I., Elson E. L. Inhibition of the mobility of mouse lymphocyte surface immunoglobulins by locally bound concanavalin A. Proc Natl Acad Sci U S A. 1981 Feb;78(2):1072–1076. doi: 10.1073/pnas.78.2.1072. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hollander N., Pillemer E., Weissman I. L. Effects of Lyt antibodies on T-cell functions: augmentation by anti-Lyt-1 as opposed to inhibition by anti-Lyt-2. Proc Natl Acad Sci U S A. 1981 Feb;78(2):1148–1151. doi: 10.1073/pnas.78.2.1148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kammer G. M., Birch R. E., Polmar S. H. Impaired immunoregulation in systemic lupus erythematosus: defective adenosine-induced suppressor T lymphocyte generation. J Immunol. 1983 Apr;130(4):1706–1712. [PubMed] [Google Scholar]
  21. Kammer G. M., Smith J. A., Mitchell R. Capping of human T cell specific determinants: kinetics of capping and receptor re-expression and regulation by the cytoskeleton. J Immunol. 1983 Jan;130(1):38–44. [PubMed] [Google Scholar]
  22. Krakauer R. S., Clough J. D., Frank S., Sundeen J. T. Suppressor cell function defect in idiopathic systemic lupus erythematosus. Clin Immunol Immunopathol. 1979 Nov;14(3):327–333. doi: 10.1016/0090-1229(79)90158-2. [DOI] [PubMed] [Google Scholar]
  23. Kuntz M. M., Innes J. B., Weksler M. E. The cellular basis of the impaired autologous mixed lymphocyte reaction in patients with systemic lupus erythematosus. J Clin Invest. 1979 Jan;63(1):151–153. doi: 10.1172/JCI109270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mandler R., Birch R. E., Polmar S. H., Kammer G. M., Rudolph S. A. Abnormal adenosine-induced immunosuppression and cAMP metabolism in T lymphocytes of patients with systemic lupus erythematosus. Proc Natl Acad Sci U S A. 1982 Dec;79(23):7542–7546. doi: 10.1073/pnas.79.23.7542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. ROPES M. W., BENNETT G. A., COBB S., JACOX R., JESSAR R. A. 1958 Revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis. 1958 Dec;9(4):175–176. [PubMed] [Google Scholar]
  26. Reinherz E. L., Schlossman S. F. Current concepts in immunology: Regulation of the immune response--inducer and suppressor T-lymphocyte subsets in human beings. N Engl J Med. 1980 Aug 14;303(7):370–373. doi: 10.1056/NEJM198008143030704. [DOI] [PubMed] [Google Scholar]
  27. Riccardi P. J., Hausman P. B., Raff H. V., Stobo J. D. The autologous mixed lymphocyte reaction in systemic lupus erythematosus. Arthritis Rheum. 1982 Jul;25(7):820–823. doi: 10.1002/art.1780250721. [DOI] [PubMed] [Google Scholar]
  28. Sagawa A., Abdou N. I. Suppressor-cell dysfunction in systemic lupus erythematosus. Cells involved and in vitro correction. J Clin Invest. 1978 Oct;62(4):789–796. doi: 10.1172/JCI109190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sakane T., Steinberg A. D., Green I. Failure of autologous mixed lymphocyte reactions between T and non-T cells in patients with systemic lupus erythematosus. Proc Natl Acad Sci U S A. 1978 Jul;75(7):3464–3468. doi: 10.1073/pnas.75.7.3464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sakane T., Steinberg A. D., Green I. Studies of immune functions of patients with systemic lupus erythematosus. I. Dysfunction of suppressor T-cell activity related to impaired generation of, rather than response to, suppressor cells. Arthritis Rheum. 1978 Jul-Aug;21(6):657–664. doi: 10.1002/art.1780210608. [DOI] [PubMed] [Google Scholar]
  31. Sakane T., Steinberg A. D., Reeves J. P., Green I. Studies of immune functions of patients with systemic lupus erythematosus. Complement-dependent immunoglobulin M anti-thymus-derived cell antibodies preferentially inactivate suppressor cells. J Clin Invest. 1979 May;63(5):954–965. doi: 10.1172/JCI109396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Schreiner G. F., Unanue E. R. Membrane and cytoplasmic changes in B lymphocytes induced by ligand-surface immunoglobulin interaction. Adv Immunol. 1976;24:37–165. doi: 10.1016/s0065-2776(08)60329-6. [DOI] [PubMed] [Google Scholar]
  33. Sidman C. L., Unanue E. R. Control of proliferation and differentiation in B lymphocytes by anti-Ig antibodies and a serum-derived cofactor. Proc Natl Acad Sci U S A. 1978 May;75(5):2401–2405. doi: 10.1073/pnas.75.5.2401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Strand V., Talal N. Advances in the diagnosis and concept of Sjögren's syndrome (autoimmune exocrinopathy). Bull Rheum Dis. 1979;30(9):1046–1052. [PubMed] [Google Scholar]
  35. Suciu-Foca N., Buda J. A., Thiem T., Reemtsma K. Impaired responsiveness of lymphocytes in patients with systemic lupus erythematosus. Clin Exp Immunol. 1974 Nov;18(3):295–301. [PMC free article] [PubMed] [Google Scholar]
  36. Van Wauwe J. P., De Mey J. R., Goossens J. G. OKT3: a monoclonal anti-human T lymphocyte antibody with potent mitogenic properties. J Immunol. 1980 Jun;124(6):2708–2713. [PubMed] [Google Scholar]
  37. Yahara I., Edelman G. M. Modulation of lymphocyte receptor redistribution by concanavalin A, anti-mitotic agents and alterations of pH. Nature. 1973 Nov 16;246(5429):152–155. doi: 10.1038/246152a0. [DOI] [PubMed] [Google Scholar]
  38. Yahara I., Edelman G. M. Restriction of the mobility of lymphocyte immunoglobulin receptors by concanavalin A. Proc Natl Acad Sci U S A. 1972 Mar;69(3):608–612. doi: 10.1073/pnas.69.3.608. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES