Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1994 Nov 1;180(5):1665–1673. doi: 10.1084/jem.180.5.1665

CD2 is involved in maintenance and reversal of human alloantigen- specific clonal anergy

PMCID: PMC2191726  PMID: 7525835

Abstract

Induction and maintenance of a state of T cell unresponsiveness to specific alloantigen would have significant implications for human organ transplantation. Using human histocompatibility leukocyte antigen DR7-specific helper T cell clones, we demonstrate that blockade of the B7 family of costimulatory molecules is sufficient to induce alloantigen-specific T cell clonal anergy. Anergized cells do not respond to alloantigen and a variety of costimulatory molecules, including B7-1, B7-2, intercellular adhesion molecule-1 (ICAM-1), and lymphocyte function-associated molecule (LFA)-3. However, after culture in exogenous interleukin (IL)-2 for at least 7 d, anergized cells can respond to alloantigen in the presence of LFA-3. LFA-3 costimulation subsequently restores responsiveness to alloantigen in the presence of previously insufficient costimulatory signals. Expression of CD2R epitope is downregulated on anergic cells and is restored after 7 d of IL-2 culture. The loss of the CD2R is temporally associated with the inability of anergized cells to respond to LFA-3. These results suggest that in addition to blockade of B7 family members, inhibition of CD2 and, potentially, other costimulatory pathways that might reverse anergy will be necessary to maintain prolonged alloantigen-specific tolerance.

Full Text

The Full Text of this article is available as a PDF (1,001.3 KB).

Selected References

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

  1. Abramson C. S., Kersey J. H., LeBien T. W. A monoclonal antibody (BA-1) reactive with cells of human B lymphocyte lineage. J Immunol. 1981 Jan;126(1):83–88. [PubMed] [Google Scholar]
  2. Augustin M., Dietrich A., Niedner R., Kapp A., Schöpf E., Ledbetter J. A., Brady W., Linsley P. S., Simon J. C. Phorbol-12-myristate-13-acetate-treated human keratinocytes express B7-like molecules that serve a costimulatory role in T-cell activation. J Invest Dermatol. 1993 Mar;100(3):275–281. doi: 10.1111/1523-1747.ep12469748. [DOI] [PubMed] [Google Scholar]
  3. Beverly B., Kang S. M., Lenardo M. J., Schwartz R. H. Reversal of in vitro T cell clonal anergy by IL-2 stimulation. Int Immunol. 1992 Jun;4(6):661–671. doi: 10.1093/intimm/4.6.661. [DOI] [PubMed] [Google Scholar]
  4. Bierer B. E., Barbosa J., Herrmann S., Burakoff S. J. Interaction of CD2 with its ligand, LFA-3, in human T cell proliferation. J Immunol. 1988 May 15;140(10):3358–3363. [PubMed] [Google Scholar]
  5. Bierer B. E., Peterson A., Gorga J. C., Herrmann S. H., Burakoff S. J. Synergistic T cell activation via the physiological ligands for CD2 and the T cell receptor. J Exp Med. 1988 Sep 1;168(3):1145–1156. doi: 10.1084/jem.168.3.1145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Boussiotis V. A., Freeman G. J., Gray G., Gribben J., Nadler L. M. B7 but not intercellular adhesion molecule-1 costimulation prevents the induction of human alloantigen-specific tolerance. J Exp Med. 1993 Nov 1;178(5):1753–1763. doi: 10.1084/jem.178.5.1753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Boussiotis V. A., Freeman G. J., Gribben J. G., Daley J., Gray G., Nadler L. M. Activated human B lymphocytes express three CTLA-4 counterreceptors that costimulate T-cell activation. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11059–11063. doi: 10.1073/pnas.90.23.11059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dallman M. J., Shiho O., Page T. H., Wood K. J., Morris P. J. Peripheral tolerance to alloantigen results from altered regulation of the interleukin 2 pathway. J Exp Med. 1991 Jan 1;173(1):79–87. doi: 10.1084/jem.173.1.79. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Essery G., Feldmann M., Lamb J. R. Interleukin-2 can prevent and reverse antigen-induced unresponsiveness in cloned human T lymphocytes. Immunology. 1988 Jul;64(3):413–417. [PMC free article] [PubMed] [Google Scholar]
  10. Freedman A. S., Freeman G. J., Rhynhart K., Nadler L. M. Selective induction of B7/BB-1 on interferon-gamma stimulated monocytes: a potential mechanism for amplification of T cell activation through the CD28 pathway. Cell Immunol. 1991 Oct 15;137(2):429–437. doi: 10.1016/0008-8749(91)90091-o. [DOI] [PubMed] [Google Scholar]
  11. Freedman A. S., Freeman G., Horowitz J. C., Daley J., Nadler L. M. B7, a B-cell-restricted antigen that identifies preactivated B cells. J Immunol. 1987 Nov 15;139(10):3260–3267. [PubMed] [Google Scholar]
  12. Freeman G. J., Borriello F., Hodes R. J., Reiser H., Hathcock K. S., Laszlo G., McKnight A. J., Kim J., Du L., Lombard D. B. Uncovering of functional alternative CTLA-4 counter-receptor in B7-deficient mice. Science. 1993 Nov 5;262(5135):907–909. doi: 10.1126/science.7694362. [DOI] [PubMed] [Google Scholar]
  13. Freeman G. J., Freedman A. S., Segil J. M., Lee G., Whitman J. F., Nadler L. M. B7, a new member of the Ig superfamily with unique expression on activated and neoplastic B cells. J Immunol. 1989 Oct 15;143(8):2714–2722. [PubMed] [Google Scholar]
  14. Freeman G. J., Gribben J. G., Boussiotis V. A., Ng J. W., Restivo V. A., Jr, Lombard L. A., Gray G. S., Nadler L. M. Cloning of B7-2: a CTLA-4 counter-receptor that costimulates human T cell proliferation. Science. 1993 Nov 5;262(5135):909–911. doi: 10.1126/science.7694363. [DOI] [PubMed] [Google Scholar]
  15. Gimmi C. D., Freeman G. J., Gribben J. G., Gray G., Nadler L. M. Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6586–6590. doi: 10.1073/pnas.90.14.6586. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gimmi C. D., Freeman G. J., Gribben J. G., Sugita K., Freedman A. S., Morimoto C., Nadler L. M. B-cell surface antigen B7 provides a costimulatory signal that induces T cells to proliferate and secrete interleukin 2. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6575–6579. doi: 10.1073/pnas.88.15.6575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Go C., Miller J. Differential induction of transcription factors that regulate the interleukin 2 gene during anergy induction and restimulation. J Exp Med. 1992 May 1;175(5):1327–1336. doi: 10.1084/jem.175.5.1327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Goronzy J., Weyand C., Fathman C. G. Cloning of human alloreactive T cells. Methods Enzymol. 1987;150:333–341. doi: 10.1016/0076-6879(87)50091-x. [DOI] [PubMed] [Google Scholar]
  19. Harding F. A., McArthur J. G., Gross J. A., Raulet D. H., Allison J. P. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature. 1992 Apr 16;356(6370):607–609. doi: 10.1038/356607a0. [DOI] [PubMed] [Google Scholar]
  20. Harper K., Balzano C., Rouvier E., Mattéi M. G., Luciani M. F., 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. 1991 Aug 1;147(3):1037–1044. [PubMed] [Google Scholar]
  21. Jenkins M. K., Ashwell J. D., Schwartz R. H. Allogeneic non-T spleen cells restore the responsiveness of normal T cell clones stimulated with antigen and chemically modified antigen-presenting cells. J Immunol. 1988 May 15;140(10):3324–3330. [PubMed] [Google Scholar]
  22. Jenkins M. K., Pardoll D. M., Mizuguchi J., Chused T. M., Schwartz R. H. Molecular events in the induction of a nonresponsive state in interleukin 2-producing helper T-lymphocyte clones. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5409–5413. doi: 10.1073/pnas.84.15.5409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kang S. M., Beverly B., Tran A. C., Brorson K., Schwartz R. H., Lenardo M. J. Transactivation by AP-1 is a molecular target of T cell clonal anergy. Science. 1992 Aug 21;257(5073):1134–1138. doi: 10.1126/science.257.5073.1134. [DOI] [PubMed] [Google Scholar]
  24. Koyasu S., Lawton T., Novick D., Recny M. A., Siliciano R. F., Wallner B. P., Reinherz E. L. Role of interaction of CD2 molecules with lymphocyte function-associated antigen 3 in T-cell recognition of nominal antigen. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2603–2607. doi: 10.1073/pnas.87.7.2603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lenschow D. J., Su G. H., Zuckerman L. A., Nabavi N., Jellis C. L., Gray G. S., Miller J., Bluestone J. A. Expression and functional significance of an additional ligand for CTLA-4. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11054–11058. doi: 10.1073/pnas.90.23.11054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Lenschow D. J., Zeng Y., Thistlethwaite J. R., Montag A., Brady W., Gibson M. G., Linsley P. S., Bluestone J. A. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science. 1992 Aug 7;257(5071):789–792. doi: 10.1126/science.1323143. [DOI] [PubMed] [Google Scholar]
  27. Lin H., Bolling S. F., Linsley P. S., Wei R. Q., Gordon D., Thompson C. B., Turka L. A. Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion. J Exp Med. 1993 Nov 1;178(5):1801–1806. doi: 10.1084/jem.178.5.1801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Linsley P. S., Brady W., Grosmaire L., Aruffo A., Damle N. K., Ledbetter J. A. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med. 1991 Mar 1;173(3):721–730. doi: 10.1084/jem.173.3.721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Linsley P. S., Brady W., Urnes M., Grosmaire L. S., Damle N. K., Ledbetter J. A. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991 Sep 1;174(3):561–569. doi: 10.1084/jem.174.3.561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Liu Y., Jones B., Aruffo A., Sullivan K. M., Linsley P. S., Janeway C. A., Jr Heat-stable antigen is a costimulatory molecule for CD4 T cell growth. J Exp Med. 1992 Feb 1;175(2):437–445. doi: 10.1084/jem.175.2.437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Meuer S. C., Hussey R. E., Fabbi M., Fox D., Acuto O., Fitzgerald K. A., Hodgdon J. C., Protentis J. P., Schlossman S. F., Reinherz E. L. An alternative pathway of T-cell activation: a functional role for the 50 kd T11 sheep erythrocyte receptor protein. Cell. 1984 Apr;36(4):897–906. doi: 10.1016/0092-8674(84)90039-4. [DOI] [PubMed] [Google Scholar]
  32. Moingeon P., Chang H. C., Wallner B. P., Stebbins C., Frey A. Z., Reinherz E. L. CD2-mediated adhesion facilitates T lymphocyte antigen recognition function. Nature. 1989 May 25;339(6222):312–314. doi: 10.1038/339312a0. [DOI] [PubMed] [Google Scholar]
  33. Mueller D. L., Jenkins M. K., Chiodetti L., Schwartz R. H. An intracellular calcium increase and protein kinase C activation fail to initiate T cell proliferation in the absence of a costimulatory signal. J Immunol. 1990 May 15;144(10):3701–3709. [PubMed] [Google Scholar]
  34. Nickoloff B. J., Mitra R. S., Lee K., Turka L. A., Green J., Thompson C., Shimizu Y. Discordant expression of CD28 ligands, BB-1, and B7 on keratinocytes in vitro and psoriatic cells in vivo. Am J Pathol. 1993 Apr;142(4):1029–1040. [PMC free article] [PubMed] [Google Scholar]
  35. Peterson A., Seed B. Monoclonal antibody and ligand binding sites of the T cell erythrocyte receptor (CD2). 1987 Oct 29-Nov 4Nature. 329(6142):842–846. doi: 10.1038/329842a0. [DOI] [PubMed] [Google Scholar]
  36. Rothlein R., Dustin M. L., Marlin S. D., Springer T. A. A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1. J Immunol. 1986 Aug 15;137(4):1270–1274. [PubMed] [Google Scholar]
  37. Sanchez-Madrid F., Krensky A. M., Ware C. F., Robbins E., Strominger J. L., Burakoff S. J., Springer T. A. Three distinct antigens associated with human T-lymphocyte-mediated cytolysis: LFA-1, LFA-2, and LFA-3. Proc Natl Acad Sci U S A. 1982 Dec;79(23):7489–7493. doi: 10.1073/pnas.79.23.7489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Schwartz R. H. A cell culture model for T lymphocyte clonal anergy. Science. 1990 Jun 15;248(4961):1349–1356. doi: 10.1126/science.2113314. [DOI] [PubMed] [Google Scholar]
  39. Selvaraj P., Plunkett M. L., Dustin M., Sanders M. E., Shaw S., Springer T. A. The T lymphocyte glycoprotein CD2 binds the cell surface ligand LFA-3. 1987 Mar 26-Apr 1Nature. 326(6111):400–403. doi: 10.1038/326400a0. [DOI] [PubMed] [Google Scholar]
  40. Symington F. W., Brady W., Linsley P. S. Expression and function of B7 on human epidermal Langerhans cells. J Immunol. 1993 Feb 15;150(4):1286–1295. [PubMed] [Google Scholar]
  41. Tan P., Anasetti C., Hansen J. A., Melrose J., Brunvand M., Bradshaw J., Ledbetter J. A., Linsley P. S. Induction of alloantigen-specific hyporesponsiveness in human T lymphocytes by blocking interaction of CD28 with its natural ligand B7/BB1. J Exp Med. 1993 Jan 1;177(1):165–173. doi: 10.1084/jem.177.1.165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Todd R. F., 3rd, Meuer S. C., Romain P. L., Schlossman S. F. A monoclonal antibody that blocks class II histocompatibility-related immune interactions. Hum Immunol. 1984 May;10(1):23–40. doi: 10.1016/0198-8859(84)90083-1. [DOI] [PubMed] [Google Scholar]
  43. Turka L. A., Linsley P. S., Lin H., Brady W., Leiden J. M., Wei R. Q., Gibson M. L., Zheng X. G., Myrdal S., Gordon D. T-cell activation by the CD28 ligand B7 is required for cardiac allograft rejection in vivo. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):11102–11105. doi: 10.1073/pnas.89.22.11102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Van Seventer G. A., Shimizu Y., Horgan K. J., Shaw S. The LFA-1 ligand ICAM-1 provides an important costimulatory signal for T cell receptor-mediated activation of resting T cells. J Immunol. 1990 Jun 15;144(12):4579–4586. [PubMed] [Google Scholar]
  45. Yang S. Y., Chouaib S., Dupont B. A common pathway for T lymphocyte activation involving both the CD3-Ti complex and CD2 sheep erythrocyte receptor determinants. J Immunol. 1986 Aug 15;137(4):1097–1100. [PubMed] [Google Scholar]
  46. Young J. W., Koulova L., Soergel S. A., Clark E. A., Steinman R. M., Dupont B. The B7/BB1 antigen provides one of several costimulatory signals for the activation of CD4+ T lymphocytes by human blood dendritic cells in vitro. J Clin Invest. 1992 Jul;90(1):229–237. doi: 10.1172/JCI115840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. de Fougerolles A. R., Springer T. A. Intercellular adhesion molecule 3, a third adhesion counter-receptor for lymphocyte function-associated molecule 1 on resting lymphocytes. J Exp Med. 1992 Jan 1;175(1):185–190. doi: 10.1084/jem.175.1.185. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES