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. 1996 Aug 1;184(2):531–537. doi: 10.1084/jem.184.2.531

Differing roles for B7 and intercellular adhesion molecule-1 in negative selection of thymocytes

PMCID: PMC2192742  PMID: 8760806

Abstract

To ensure self tolerance, immature thymocytes with high binding affinity for self peptides linked to major histocompatibility complex (MHC) molecules are eliminated in situ via apoptosis (negative selection). The roles of two costimulatory molecules, B7-1 and intercellular adhesion molecule-1 (ICAM-1), in negative selection was examined by studying apoptosis of T cell receptor transgenic CD4+8+ thymocytes cultured with specific peptides presented by MHC class I- transfected Drosophila cells. When coexpressed on these cells, B7-1 and ICAM-1 act synergistically and cause strong class 1-restricted negative selection of thymocytes. When expressed separately, however, B7-1 and ICAM-1 display opposite functions: negative selection is augmented by B7-1, but is inhibited by ICAM-1. It is notable that B7-1 is expressed selectively in the thymic medulla, whereas ICAM-1 is expressed throughout the thymus. Because of this distribution, the differing functions of B7-1 and ICAM-1 may dictate the sites of positive and negative selection. Thus, in the cortex, the presence of ICAM-1, but not B7-1, on the cortical epithelium may preclude or reduce negative selection and thereby promote positive selection. Conversely, the combined expression of B7-1 and ICAM-1 may define the medulla as the principal site of negative selection.

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Selected References

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

  1. Aiba Y., Mazda O., Davis M. M., Muramatsu S., Katsura Y. Requirement of a second signal from antigen presenting cells in the clonal deletion of immature T cells. Int Immunol. 1994 Oct;6(10):1475–1483. doi: 10.1093/intimm/6.10.1475. [DOI] [PubMed] [Google Scholar]
  2. Amakawa R., Hakem A., Kundig T. M., Matsuyama T., Simard J. J., Timms E., Wakeham A., Mittruecker H. W., Griesser H., Takimoto H. Impaired negative selection of T cells in Hodgkin's disease antigen CD30-deficient mice. Cell. 1996 Feb 23;84(4):551–562. doi: 10.1016/s0092-8674(00)81031-4. [DOI] [PubMed] [Google Scholar]
  3. Corr M., Slanetz A. E., Boyd L. F., Jelonek M. T., Khilko S., al-Ramadi B. K., Kim Y. S., Maher S. E., Bothwell A. L., Margulies D. H. T cell receptor-MHC class I peptide interactions: affinity, kinetics, and specificity. Science. 1994 Aug 12;265(5174):946–949. doi: 10.1126/science.8052850. [DOI] [PubMed] [Google Scholar]
  4. Cory S. Regulation of lymphocyte survival by the bcl-2 gene family. Annu Rev Immunol. 1995;13:513–543. doi: 10.1146/annurev.iy.13.040195.002501. [DOI] [PubMed] [Google Scholar]
  5. Degermann S., Surh C. D., Glimcher L. H., Sprent J., Lo D. B7 expression on thymic medullary epithelium correlates with epithelium-mediated deletion of V beta 5+ thymocytes. J Immunol. 1994 Apr 1;152(7):3254–3263. [PubMed] [Google Scholar]
  6. Fowlkes B. J., Ramsdell F. T-cell tolerance. Curr Opin Immunol. 1993 Dec;5(6):873–879. doi: 10.1016/0952-7915(93)90099-e. [DOI] [PubMed] [Google Scholar]
  7. Foy T. M., Page D. M., Waldschmidt T. J., Schoneveld A., Laman J. D., Masters S. R., Tygrett L., Ledbetter J. A., Aruffo A., Claassen E. An essential role for gp39, the ligand for CD40, in thymic selection. J Exp Med. 1995 Nov 1;182(5):1377–1388. doi: 10.1084/jem.182.5.1377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gavrieli Y., Sherman Y., Ben-Sasson S. A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. doi: 10.1083/jcb.119.3.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Jackson M. R., Song E. S., Yang Y., Peterson P. A. Empty and peptide-containing conformers of class I major histocompatibility complex molecules expressed in Drosophila melanogaster cells. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12117–12121. doi: 10.1073/pnas.89.24.12117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Janeway C. A., Jr, Bottomly K. Signals and signs for lymphocyte responses. Cell. 1994 Jan 28;76(2):275–285. doi: 10.1016/0092-8674(94)90335-2. [DOI] [PubMed] [Google Scholar]
  11. Kishimoto H., Surh C. D., Sprent J. Upregulation of surface markers on dying thymocytes. J Exp Med. 1995 Feb 1;181(2):649–655. doi: 10.1084/jem.181.2.649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Koopman G., Keehnen R. M., Lindhout E., Newman W., Shimizu Y., van Seventer G. A., de Groot C., Pals S. T. Adhesion through the LFA-1 (CD11a/CD18)-ICAM-1 (CD54) and the VLA-4 (CD49d)-VCAM-1 (CD106) pathways prevents apoptosis of germinal center B cells. J Immunol. 1994 Apr 15;152(8):3760–3767. [PubMed] [Google Scholar]
  13. Kosaka H., Surh C. D., Sprent J. Stimulation of mature unprimed CD8+ T cells by semiprofessional antigen-presenting cells in vivo. J Exp Med. 1992 Nov 1;176(5):1291–1302. doi: 10.1084/jem.176.5.1291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Krajewski S., Krajewska M., Shabaik A., Miyashita T., Wang H. G., Reed J. C. Immunohistochemical determination of in vivo distribution of Bax, a dominant inhibitor of Bcl-2. Am J Pathol. 1994 Dec;145(6):1323–1336. [PMC free article] [PubMed] [Google Scholar]
  15. Krajewski S., Krajewska M., Shabaik A., Wang H. G., Irie S., Fong L., Reed J. C. Immunohistochemical analysis of in vivo patterns of Bcl-X expression. Cancer Res. 1994 Nov 1;54(21):5501–5507. [PubMed] [Google Scholar]
  16. Linsley P. S., Ledbetter J. A. The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol. 1993;11:191–212. doi: 10.1146/annurev.iy.11.040193.001203. [DOI] [PubMed] [Google Scholar]
  17. Marlin S. D., Springer T. A. Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1 (LFA-1). Cell. 1987 Dec 4;51(5):813–819. doi: 10.1016/0092-8674(87)90104-8. [DOI] [PubMed] [Google Scholar]
  18. Nagata S., Suda T. Fas and Fas ligand: lpr and gld mutations. Immunol Today. 1995 Jan;16(1):39–43. doi: 10.1016/0167-5699(95)80069-7. [DOI] [PubMed] [Google Scholar]
  19. Nelson A. J., Hosier S., Brady W., Linsley P. S., Farr A. G. Medullary thymic epithelium expresses a ligand for CTLA4 in situ and in vitro. J Immunol. 1993 Sep 1;151(5):2453–2461. [PubMed] [Google Scholar]
  20. Page D. M., Kane L. P., Allison J. P., Hedrick S. M. Two signals are required for negative selection of CD4+CD8+ thymocytes. J Immunol. 1993 Aug 15;151(4):1868–1880. [PubMed] [Google Scholar]
  21. Prieto J., Takei F., Gendelman R., Christenson B., Biberfeld P., Patarroyo M. MALA-2, mouse homologue of human adhesion molecule ICAM-1 (CD54). Eur J Immunol. 1989 Sep;19(9):1551–1557. doi: 10.1002/eji.1830190906. [DOI] [PubMed] [Google Scholar]
  22. Punt J. A., Osborne B. A., Takahama Y., Sharrow S. O., Singer A. Negative selection of CD4+CD8+ thymocytes by T cell receptor-induced apoptosis requires a costimulatory signal that can be provided by CD28. J Exp Med. 1994 Feb 1;179(2):709–713. doi: 10.1084/jem.179.2.709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Rosenstein Y., Park J. K., Hahn W. C., Rosen F. S., Bierer B. E., Burakoff S. J. CD43, a molecule defective in Wiskott-Aldrich syndrome, binds ICAM-1. Nature. 1991 Nov 21;354(6350):233–235. doi: 10.1038/354233a0. [DOI] [PubMed] [Google Scholar]
  24. Schwartz R. H. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell. 1992 Dec 24;71(7):1065–1068. doi: 10.1016/s0092-8674(05)80055-8. [DOI] [PubMed] [Google Scholar]
  25. Sha W. C., Nelson C. A., Newberry R. D., Kranz D. M., Russell J. H., Loh D. Y. Selective expression of an antigen receptor on CD8-bearing T lymphocytes in transgenic mice. Nature. 1988 Sep 15;335(6187):271–274. doi: 10.1038/335271a0. [DOI] [PubMed] [Google Scholar]
  26. Shahinian A., Pfeffer K., Lee K. P., Kündig T. M., Kishihara K., Wakeham A., Kawai K., Ohashi P. S., Thompson C. B., Mak T. W. Differential T cell costimulatory requirements in CD28-deficient mice. Science. 1993 Jul 30;261(5121):609–612. doi: 10.1126/science.7688139. [DOI] [PubMed] [Google Scholar]
  27. Singer K. H. Interactions between epithelial cells and T lymphocytes: role of adhesion molecules. J Leukoc Biol. 1990 Oct;48(4):367–374. doi: 10.1002/jlb.48.4.367. [DOI] [PubMed] [Google Scholar]
  28. Sprent J., Webb S. R. Intrathymic and extrathymic clonal deletion of T cells. Curr Opin Immunol. 1995 Apr;7(2):196–205. doi: 10.1016/0952-7915(95)80004-2. [DOI] [PubMed] [Google Scholar]
  29. Sumimoto S., Heike T., Kanazashi S., Shintaku N., Jung E. Y., Hata D., Katamura K., Mayumi M. Involvement of LFA-1/intracellular adhesion molecule-1-dependent cell adhesion in CD40-mediated inhibition of human B lymphoma cell death induced by surface IgM crosslinking. J Immunol. 1994 Sep 15;153(6):2488–2496. [PubMed] [Google Scholar]
  30. Sykulev Y., Brunmark A., Jackson M., Cohen R. J., Peterson P. A., Eisen H. N. Kinetics and affinity of reactions between an antigen-specific T cell receptor and peptide-MHC complexes. Immunity. 1994 Apr;1(1):15–22. doi: 10.1016/1074-7613(94)90005-1. [DOI] [PubMed] [Google Scholar]
  31. Sykulev Y., Brunmark A., Tsomides T. J., Kageyama S., Jackson M., Peterson P. A., Eisen H. N. High-affinity reactions between antigen-specific T-cell receptors and peptides associated with allogeneic and syngeneic major histocompatibility complex class I proteins. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11487–11491. doi: 10.1073/pnas.91.24.11487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Tan R., Teh S. J., Ledbetter J. A., Linsley P. S., Teh H. S. B7 costimulates proliferation of CD4-8+ T lymphocytes but is not required for the deletion of immature CD4+8+ thymocytes. J Immunol. 1992 Nov 15;149(10):3217–3224. [PubMed] [Google Scholar]
  33. Udaka K., Tsomides T. J., Eisen H. N. A naturally occurring peptide recognized by alloreactive CD8+ cytotoxic T lymphocytes in association with a class I MHC protein. Cell. 1992 Jun 12;69(6):989–998. doi: 10.1016/0092-8674(92)90617-l. [DOI] [PubMed] [Google Scholar]
  34. Udaka K., Tsomides T. J., Walden P., Fukusen N., Eisen H. N. A ubiquitous protein is the source of naturally occurring peptides that are recognized by a CD8+ T-cell clone. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11272–11276. doi: 10.1073/pnas.90.23.11272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Yang Y., Früh K., Chambers J., Waters J. B., Wu L., Spies T., Peterson P. A. Major histocompatibility complex (MHC)-encoded HAM2 is necessary for antigenic peptide loading onto class I MHC molecules. J Biol Chem. 1992 Jun 15;267(17):11669–11672. [PubMed] [Google Scholar]
  36. Zhao Y., Iwata M. Cross-linking of the TCR-CD3 complex with CD4, CD8 or LFA-1 induces an anti-apoptotic signal in thymocytes: the signal is canceled by FK506. Int Immunol. 1995 Sep;7(9):1387–1396. doi: 10.1093/intimm/7.9.1387. [DOI] [PubMed] [Google Scholar]

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