Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1993 Sep 1;178(3):769–776. doi: 10.1084/jem.178.3.769

Antibodies against major histocompatibility complex class II antigens directly inhibit the growth of T cells infected with Theileria parva without affecting their state of activation

PMCID: PMC2191146  PMID: 8350052

Abstract

We have analyzed the effect of antibodies (Abs) directed against major histocompatibility complex (MHC) class II Abs on the proliferation of Theileria parva-infected (Tpi) T cells. Anti-MHC class II Abs exert a direct effect on Tpi T cells causing an acute block in their proliferation. The inhibition does not involve apoptosis and is also entirely reversible. The rapid arrest of DNA synthesis caused by anti- MHC class II Abs is not due to interference with the state of activation of the T cells since the transcriptional activator NF-kappa B remains activated in arrested cells. In addition, interleukin 2 (IL- 2), IL-2R, and c-myc gene expression are also unaffected. By analyzing the cell-cycle phase distribution of inhibited cells, it could be shown that cells in all phases of the cell cycle are inhibited. The signal transduction pathway that results in inhibition was shown to be independent of protein kinase C and extracellular Ca2+. Tyrosine kinase inhibitors, however, partly reduced the level of inhibition and, conversely, phosphatase inhibitors enhanced it. The possible relevance of this phenomenon in other systems is discussed.

Full Text

The Full Text of this article is available as a PDF (958.4 KB).

Selected References

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

  1. Ashwell J. D., Cunningham R. E., Noguchi P. D., Hernandez D. Cell growth cycle block of T cell hybridomas upon activation with antigen. J Exp Med. 1987 Jan 1;165(1):173–194. doi: 10.1084/jem.165.1.173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Beckwith M., Urba W. J., Ferris D. K., Freter C. E., Kuhns D. B., Moratz C. M., Longo D. L. Anti-IgM-mediated growth inhibition of a human B lymphoma cell line is independent of phosphatidylinositol turnover and protein kinase C activation and involves tyrosine phosphorylation. J Immunol. 1991 Oct 1;147(7):2411–2418. [PubMed] [Google Scholar]
  3. Bishop G. A., Haughton G. Induced differentiation of a transformed clone of Ly-1+ B cells by clonal T cells and antigen. Proc Natl Acad Sci U S A. 1986 Oct;83(19):7410–7414. doi: 10.1073/pnas.83.19.7410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Breitmeyer J. B., Oppenheim S. O., Daley J. F., Levine H. B., Schlossman S. F. Growth inhibition of human T cells by antibodies recognizing the T cell antigen receptor complex. J Immunol. 1987 Feb 1;138(3):726–731. [PubMed] [Google Scholar]
  5. Böhnlein E., Lowenthal J. W., Siekevitz M., Ballard D. W., Franza B. R., Greene W. C. The same inducible nuclear proteins regulates mitogen activation of both the interleukin-2 receptor-alpha gene and type 1 HIV. Cell. 1988 Jun 3;53(5):827–836. doi: 10.1016/0092-8674(88)90099-2. [DOI] [PubMed] [Google Scholar]
  6. Cambier J. C., Newell M. K., Justement L. B., McGuire J. C., Leach K. L., Chen Z. Z. Ia binding ligands and cAMP stimulate nuclear translocation of PKC in B lymphocytes. Nature. 1987 Jun 18;327(6123):629–632. doi: 10.1038/327629a0. [DOI] [PubMed] [Google Scholar]
  7. Coquerelle T. M., Eichhorn M., Magnuson N. S., Reeves R., Williams R. O., Dobbelaere D. A. Expression and characterization of the interleukin 2 receptor in Theileria parva-infected bovine lymphocytes. Eur J Immunol. 1989 Apr;19(4):655–659. doi: 10.1002/eji.1830190413. [DOI] [PubMed] [Google Scholar]
  8. Dobbelaere D. A., Coquerelle T. M., Roditi I. J., Eichhorn M., Williams R. O. Theileria parva infection induces autocrine growth of bovine lymphocytes. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4730–4734. doi: 10.1073/pnas.85.13.4730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dobbelaere D. A., Prospero T. D., Roditi I. J., Kelke C., Baumann I., Eichhorn M., Williams R. O., Ahmed J. S., Baldwin C. L., Clevers H. Expression of Tac antigen component of bovine interleukin-2 receptor in different leukocyte populations infected with Theileria parva or Theileria annulata. Infect Immun. 1990 Dec;58(12):3847–3855. doi: 10.1128/iai.58.12.3847-3855.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Eichhorn M., Magnuson N. S., Reeves R., Williams R. O., Dobbelaere D. A. IL-2 can enhance the cyclosporin A-mediated inhibition of Theileria parva-infected T cell proliferation. J Immunol. 1990 Jan 15;144(2):691–698. [PubMed] [Google Scholar]
  11. Forsgren S., Pobor G., Coutinho A., Pierres M. The role of I-A/E molecules in B lymphocyte activation. I. Inhibition of lipopolysaccharide-induced responses by monoclonal antibodies. J Immunol. 1984 Oct;133(4):2104–2110. [PubMed] [Google Scholar]
  12. Golding H., Robey F. A., Gates F. T., 3rd, Linder W., Beining P. R., Hoffman T., Golding B. Identification of homologous regions in human immunodeficiency virus I gp41 and human MHC class II beta 1 domain. I. Monoclonal antibodies against the gp41-derived peptide and patients' sera react with native HLA class II antigens, suggesting a role for autoimmunity in the pathogenesis of acquired immune deficiency syndrome. J Exp Med. 1988 Mar 1;167(3):914–923. doi: 10.1084/jem.167.3.914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Heussler V. T., Eichhorn M., Reeves R., Magnuson N. S., Williams R. O., Dobbelaere D. A. Constitutive IL-2 mRNA expression in lymphocytes, infected with the intracellular parasite Theileria parva. J Immunol. 1992 Jul 15;149(2):562–567. [PubMed] [Google Scholar]
  14. Hoyos B., Ballard D. W., Böhnlein E., Siekevitz M., Greene W. C. Kappa B-specific DNA binding proteins: role in the regulation of human interleukin-2 gene expression. Science. 1989 Apr 28;244(4903):457–460. doi: 10.1126/science.2497518. [DOI] [PubMed] [Google Scholar]
  15. Ivanov V., Stein B., Baumann I., Dobbelaere D. A., Herrlich P., Williams R. O. Infection with the intracellular protozoan parasite Theileria parva induces constitutively high levels of NF-kappa B in bovine T lymphocytes. Mol Cell Biol. 1989 Nov;9(11):4677–4686. doi: 10.1128/mcb.9.11.4677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kabelitz D., Janssen O. Growth inhibition of Epstein-Barr virus-transformed B cells by anti-HLA-DR antibody L243: possible relationship to L243-induced down-regulation of CD23 antigen expression. Cell Immunol. 1989 Apr 15;120(1):21–30. doi: 10.1016/0008-8749(89)90171-8. [DOI] [PubMed] [Google Scholar]
  17. Kansas G. S., Tedder T. F. Transmembrane signals generated through MHC class II, CD19, CD20, CD39, and CD40 antigens induce LFA-1-dependent and independent adhesion in human B cells through a tyrosine kinase-dependent pathway. J Immunol. 1991 Dec 15;147(12):4094–4102. [PubMed] [Google Scholar]
  18. Kornfeld H., Cruikshank W. W., Pyle S. W., Berman J. S., Center D. M. Lymphocyte activation by HIV-1 envelope glycoprotein. Nature. 1988 Sep 29;335(6189):445–448. doi: 10.1038/335445a0. [DOI] [PubMed] [Google Scholar]
  19. Lane P. J., McConnell F. M., Schieven G. L., Clark E. A., Ledbetter J. A. The role of class II molecules in human B cell activation. Association with phosphatidyl inositol turnover, protein tyrosine phosphorylation, and proliferation. J Immunol. 1990 May 15;144(10):3684–3692. [PubMed] [Google Scholar]
  20. Merćep M., Bluestone J. A., Noguchi P. D., Ashwell J. D. Inhibition of transformed T cell growth in vitro by monoclonal antibodies directed against distinct activating molecules. J Immunol. 1988 Jan 1;140(1):324–335. [PubMed] [Google Scholar]
  21. Mooney N. A., Grillot-Courvalin C., Hivroz C., Ju L. Y., Charron D. Early biochemical events after MHC class II-mediated signaling on human B lymphocytes. J Immunol. 1990 Oct 1;145(7):2070–2076. [PubMed] [Google Scholar]
  22. Moretta A., Accolla R. S., Cerottini J. C. IL-2-mediated T cell proliferation in humans is blocked by a monoclonal antibody directed against monomorphic determinants of HLA-DR antigens. J Exp Med. 1982 Feb 1;155(2):599–604. doi: 10.1084/jem.155.2.599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mourad W., Geha R. S., Chatila T. Engagement of major histocompatibility complex class II molecules induces sustained, lymphocyte function-associated molecule 1-dependent cell adhesion. J Exp Med. 1990 Nov 1;172(5):1513–1516. doi: 10.1084/jem.172.5.1513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Nabavi N., Ghogawala Z., Myer A., Griffith I. J., Wade W. F., Chen Z. Z., McKean D. J., Glimcher L. H. Antigen presentation abrogated in cells expressing truncated Ia molecules. J Immunol. 1989 Mar 1;142(5):1444–1447. [PubMed] [Google Scholar]
  25. Odum N., Martin P. J., Schieven G. L., Hansen J. A., Ledbetter J. A. Signal transduction by HLA class II antigens expressed on activated T cells. Eur J Immunol. 1991 Jan;21(1):123–129. doi: 10.1002/eji.1830210119. [DOI] [PubMed] [Google Scholar]
  26. Okudaira K., Searles R. P., Goodwin J. S., Williams R. C., Jr Antibodies in the sera of patients with systemic lupus erythematosus that block the binding of monoclonal anti-Ia to Ia-positive targets also inhibit the autologous mixed lymphocyte response. J Immunol. 1982 Aug;129(2):582–586. [PubMed] [Google Scholar]
  27. Racioppi L., Moscarella A., Ruggiero G., Manzo C., Ferrone S., Fontana S., Zappacosta S. Inhibition by anti-HLA class II monoclonal antibodies of monoclonal antibody OKT3-induced T cell proliferation. Studies at the mRNA level. J Immunol. 1990 Dec 1;145(11):3635–3640. [PubMed] [Google Scholar]
  28. Ruggiero G., Manzo C., Fontana S., Scala G., Pirozzi G., Ferrone S., Zappacosta S. Inhibition by anti-HLA class II monoclonal antibodies of monocyte-dependent T cell proliferation induced by monoclonal antibody OKT3. Eur J Immunol. 1987 Nov;17(11):1585–1592. doi: 10.1002/eji.1830171110. [DOI] [PubMed] [Google Scholar]
  29. Spertini F., Chatila T., Geha R. S. Signals delivered via MHC class II molecules synergize with signals delivered via TCR/CD3 to cause proliferation and cytokine gene expression in T cells. J Immunol. 1992 Jul 1;149(1):65–70. [PubMed] [Google Scholar]
  30. St-Pierre Y., Nabavi N., Ghogawala Z., Glimcher L. H., Watts T. H. A functional role for signal transduction via the cytoplasmic domains of MHC class II proteins. J Immunol. 1989 Aug 1;143(3):808–812. [PubMed] [Google Scholar]
  31. Stein B., Rahmsdorf H. J., Steffen A., Litfin M., Herrlich P. UV-induced DNA damage is an intermediate step in UV-induced expression of human immunodeficiency virus type 1, collagenase, c-fos, and metallothionein. Mol Cell Biol. 1989 Nov;9(11):5169–5181. doi: 10.1128/mcb.9.11.5169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Turco M. C., de Felice M., Corbo L., Giarrusso P. C., Yang S. Y., Ferrone S., Venuta S. Enhancing effect of anti-HLA class I monoclonal antibodies on T cell proliferation induced via CD2 molecule. J Immunol. 1988 Oct 1;141(7):2275–2281. [PubMed] [Google Scholar]
  33. Vaickus L., Jones V. E., Morton C. L., Whitford K., Bacon R. N. Antiproliferative mechanism of anti-class II monoclonal antibodies. Cell Immunol. 1989 Apr 1;119(2):445–458. doi: 10.1016/0008-8749(89)90257-8. [DOI] [PubMed] [Google Scholar]
  34. Young J. A. HIV and HLA similarity. Nature. 1988 May 19;333(6170):215–215. doi: 10.1038/333215c0. [DOI] [PubMed] [Google Scholar]

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

RESOURCES