Journal of Clinical Immunology

, Volume 18, Issue 6, pp 392–398 | Cite as

Expression of CTLA-4 Molecule in Peripheral Blood T Lymphocytes from Patients with Systemic Lupus Erythematosus

  • Ming-Fei Liu
  • Hsiao-Sheng Liu
  • Chrong-Reen Wang
  • Huan-Yao Lei


CTLA-4 is a cell surface molecule expressed on activated T cells that is suggested to deliver a negative signal for T cell activation. Since CTLA-4 might be a negative regulator of autoimmune diseases, we investigated its expression on T cells from 20 patients with systemic lupus erythematosus (SLE) by flow cytometric analysis and RT-PCR. We found that although CTLA-4 mRNA was readily detected in all patients and controls, only a very minor subset of T cells expressed detectable surface CTLA-4 molecules in both groups. But patients with SLE had significantly increased percentages of CTLA-4-positive T cells compared with normal controls, implying at least that there was no apparent defective expression of CTLA-4 molecule in human lupus. The kinetics of CTLA-4 expression on T cells stimulated in vitro with PMA plus ionomycin were similar in normal controls and patients with SLE. The expression of CTLA-4 molecules after stimulation increased gradually and peaked at 72 hr. However, the induction of CTLA-4 expression on patients' T cells appeared to be weaker than that of normal individuals. Whether this reflects impaired down regulation by CTLA-4 molecules in SLE patients needs to be clarified further.

CTLA-4 T cells systemic lupus erythematosus 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Allison JP: CD28-B7 interaction in T-cell activation. Curr Opin Immunol 6:414–419, 1994Google Scholar
  2. 2.
    Linsley PS, Ledbetter JA: The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol 11:191–212, 1993Google Scholar
  3. 3.
    Lenschow DJ, Walunas TL, Bluestone JA: CD28/B7 system of T cell costimulation. Annu Rev Immunol 14:233–258, 1996Google Scholar
  4. 4.
    Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, Golstein P: A new member of the immunoglobulin superfamily-CTLA-4. Nature 328:267–270, 1987Google Scholar
  5. 5.
    Harper K, Balzano C, Rouvier E, Matti MG, Luciani MF, Golstein P: CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location. J Immunol 147:1037–1044, 1991Google Scholar
  6. 6.
    Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA: CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 174:561–569, 1991Google Scholar
  7. 7.
    Linsley PS, Greene JL, Brady W, Bajorath J, Ledbetter JA, Peach R: Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1:793–801, 1994Google Scholar
  8. 8.
    Linsley PS, Greene JL, Tan P, Bradshaw J, Ledbetter JA, Anasatti C, Damle NK: Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J Exp Med 176:1595–1604, 1992Google Scholar
  9. 9.
    Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, Thompson CB, Bluestone JA: CTLA-4 can function as a negative regulator of T cell activation. Immunity 1:405–413, 1994Google Scholar
  10. 10.
    Krummel MF, Allison JP: CD28 and CTLA-4 deliver opposing signals which regulate the response of T cells to stimulation. J Exp Med 182:459–466, 1995Google Scholar
  11. 11.
    Krummel MF, Allison JP: CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J Exp Med 183:2533–2540, 1996Google Scholar
  12. 12.
    Walunas TL, Bakker CY, Bluestone JA: CTLA-4 ligation blocks CD28-dependent T cell activation. J Exp Med 183:2541–2550, 1996Google Scholar
  13. 13.
    June CH, Bluestone JA, Nadler LM, Thompson CB: The B7 and CD28 receptor families. Immunol Today 15:321–331, 1994Google Scholar
  14. 14.
    Waterhouse P, Penninger JM, Timms Emma, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW: Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science 270:985–988, 1995Google Scholar
  15. 15.
    Karandikar NJ, Vanderlugt CL, Walunas TL, Miller SD, Bluestone JA: CTLA-4: A negative regulator of autoimmune disease. J Exp Med 184:783–788, 1996Google Scholar
  16. 16.
    Perrin PJ, Maldonado JH, Davis TA, June CH, Racke MK: CTLA-4 blockage enhances clinical disease and cytokine production during experimental allergic encephalomyelitis. J Immunol 157:1333–1336, 1996Google Scholar
  17. 17.
    Luhder F, Hoglund P, Allison JP, Benoist C, Mathis D: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes. J Exp Med 187:427–432, 1998Google Scholar
  18. 18.
    Liu Y: Is CTLA-4 a negative regulator for T-cell activation? Immunol Today 18:569–572, 1997Google Scholar
  19. 19.
    Thompson CB, Allison JP: The emerging role of CTLA-4 as an immune attenuator. Immunity 7:445–450, 1997Google Scholar
  20. 20.
    Verwilghen J, Lovis R, De Bor M, Linsley PS, Haines GK, Koch AE, Pope RM: Expression of functional B7 and CTLA-4 on rheumatoid synovial T cells. J Immunol 153:1378–1385, 1994Google Scholar
  21. 21.
    Yanagawa T, Hidaka Y, Guimaraes V, Soliman M, Degroot LJ: CTLA-4 gene polymorphism associated with Graves' disease in a Caucasian population. J Clin Endocrinol Metab 80:41–45, 1995Google Scholar
  22. 22.
    Donner H, Rau H, Walfish PG, Braun J, Siegmund T, Finke R, Herwig J, Usadel KH, Badenhoop K: CTLA-4 alanine-17 confers genetic susceptibility to Graves' disease and to type 1 diabetes mellitus. J Clin Endocrinol Metab 82:143–146, 1997Google Scholar
  23. 23.
    Chuang E, Alegre ML, Duckett CS, Noel PJ, Vander Heiden MG, Thompson CB: Interaction of CTLA-4 with the clathrin-associated protein AP50 in ligand-independent endocytosis that limits cell surface expression. J Immunol 159:144–151, 1997Google Scholar
  24. 24.
    Shiratori T, Miyatake S, Ohno H, Nakaseko C, Isono K, Bonifacino JS, Saito T: Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrinassociated adaptor complex AP-2. Immunity 6:583–589, 1997Google Scholar
  25. 25.
    Alegre ML, Noel PJ, Eisfelder BJ, Chuang E, Clark MR, Reiner SL, Thompson CB: Regulation of surface and intracellular expression of CTLA-4 on mouse T cells. J Immunol 157:4762–4770, 1996Google Scholar
  26. 26.
    Rosenthal CJ, Franklin EC: Depression of cellular-mediated immunity in systemic lupus erythematosus. Relation to disease activity. Arth Rheum 18:207–217, 1975Google Scholar
  27. 27.
    Gottlieb AB, Lahita RG, Chiorazzi N, Kunkel HG: Immune function in systemic lupus erythematosus. Impairment of in vitro T cell proliferation and in vivo antibody response to exogenous antigen. J Clin Invest 63:885–892, 1979Google Scholar
  28. 28.
    Kuntz MM, Innes JB, Weksler ME: The cellular basis of the impaired autologous mixed lymphocyte reaction in patients with systemic lupus erythematosus. J Clin Invest 63:151–153, 1979Google Scholar
  29. 29.
    Garcia-Cozar FJ, Molina MJ, Cuadrado MJ, Marubayashi M, Pena J, Santamaria M: Defective B7 expression on antigen-presenting cells underlying T cell activation abnormalities in systemic lupus erythematosus patients. Clin Exp Immunol 104:72–79, 1996Google Scholar
  30. 30.
    Tsokos GC, Kovacs B, Sfikakis PP, Theocharis S, Vogelgesang S, Via CS: Defective antigen-presenting cell function in patients with systemic lupus erythematosus. Role of the B7-1 (CD80) costimulatory molecule. Arth Rheum 39:600–609, 1996Google Scholar
  31. 31.
    Liu MF, Li JS, Weng TH, Lei HY: Differential expression and modulation of costimulatory molecules CD80 and CD86 on monocytes from patients with systemic lupus erythematosus. Scand J Immunol (in press), 1998Google Scholar

Copyright information

© Plenum Publishing Corporation 1998

Authors and Affiliations

  • Ming-Fei Liu
    • 1
  • Hsiao-Sheng Liu
    • 1
  • Chrong-Reen Wang
    • 2
  • Huan-Yao Lei
  1. 1.Section of Rheumatology and Immunology, Department of Internal Medicine, College of MedicineNational Cheng Kung UniversityTainan, TaiwanR.O.C
  2. 2.Section of Rheumatology and Immunology, Department of Internal Medicine, College of MedicineNational Taiwan UniversityTaipei, TaiwanR.O.C

Personalised recommendations