Abstract
CTLA-4, a coreceptor with sequence homology to CD28 is expressed on T cells after activation. Mice deficient for CTLA-4 die young from massive infiltration of many organs by activated T cells, which highlights the essential inhibitory role the coreceptor plays in the regulation of the immune response. To study the prevalence and distribution of CTLA-4 in situ immunohistological analyses were carried out on human tonsils and lymph nodes. Expression of CTLA-4 was restricted to alpha beta T cells, and CTLA-4+ B cells were not observed. In T-cell areas, 2-10% of T cells were positive for CTLA-4 with similar percentages in the CD4+ and CD8+ subpopulations. In the germinal centres (GC) the fraction of CTLA-4+ T cells was much higher (70-90%). This was due to frequent expression of CTLA-4 on the CD4+ helper subpopulation. GC CD8+ T cells were rare and mostly did not express the coreceptor. The CTLA-4+ T-cell fraction was also over-represented among intraepithelial tonsillar T cells. Cycling (Ki-67+) and apoptotic (TUNEL+) T cells were never positive for CTLA-4, while a subset of CD25+ cells did express the coreceptor. Since CTLA-4 is essential for the physiological limitation of the immune response, GC T cells, which are mostly CTLA-4 positive, might be important in this process.
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- Allison J. P., Krummel M. F. The Yin and Yang of T cell costimulation. Science. 1995 Nov 10;270(5238):932–933. doi: 10.1126/science.270.5238.932. [DOI] [PubMed] [Google Scholar]
- Boussiotis V. A., Gribben J. G., Freeman G. J., Nadler L. M. Blockade of the CD28 co-stimulatory pathway: a means to induce tolerance. Curr Opin Immunol. 1994 Oct;6(5):797–807. doi: 10.1016/0952-7915(94)90087-6. [DOI] [PubMed] [Google Scholar]
- Brunet J. F., Denizot F., Luciani M. F., Roux-Dosseto M., Suzan M., Mattei M. G., Golstein P. A new member of the immunoglobulin superfamily--CTLA-4. Nature. 1987 Jul 16;328(6127):267–270. doi: 10.1038/328267a0. [DOI] [PubMed] [Google Scholar]
- Callard R. E., Armitage R. J., Fanslow W. C., Spriggs M. K. CD40 ligand and its role in X-linked hyper-IgM syndrome. Immunol Today. 1993 Nov;14(11):559–564. doi: 10.1016/0167-5699(93)90188-Q. [DOI] [PubMed] [Google Scholar]
- Dariavach P., Mattéi M. G., Golstein P., Lefranc M. P. Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains. Eur J Immunol. 1988 Dec;18(12):1901–1905. doi: 10.1002/eji.1830181206. [DOI] [PubMed] [Google Scholar]
- Foy T. M., Laman J. D., Ledbetter J. A., Aruffo A., Claassen E., Noelle R. J. gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory. J Exp Med. 1994 Jul 1;180(1):157–163. doi: 10.1084/jem.180.1.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Freeman G. J., Lombard D. B., Gimmi C. D., Brod S. A., Lee K., Laning J. C., Hafler D. A., Dorf M. E., Gray G. S., Reiser H. CTLA-4 and CD28 mRNA are coexpressed in most T cells after activation. Expression of CTLA-4 and CD28 mRNA does not correlate with the pattern of lymphokine production. J Immunol. 1992 Dec 15;149(12):3795–3801. [PubMed] [Google Scholar]
- 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]
- Gerdes J., Lemke H., Baisch H., Wacker H. H., Schwab U., Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984 Oct;133(4):1710–1715. [PubMed] [Google Scholar]
- Gribben J. G., Freeman G. J., Boussiotis V. A., Rennert P., Jellis C. L., Greenfield E., Barber M., Restivo V. A., Jr, Ke X., Gray G. S. CTLA4 mediates antigen-specific apoptosis of human T cells. Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):811–815. doi: 10.1073/pnas.92.3.811. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Han S., Hathcock K., Zheng B., Kepler T. B., Hodes R., Kelsoe G. Cellular interaction in germinal centers. Roles of CD40 ligand and B7-2 in established germinal centers. J Immunol. 1995 Jul 15;155(2):556–567. [PubMed] [Google Scholar]
- 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]
- June C. H., Bluestone J. A., Nadler L. M., Thompson C. B. The B7 and CD28 receptor families. Immunol Today. 1994 Jul;15(7):321–331. doi: 10.1016/0167-5699(94)90080-9. [DOI] [PubMed] [Google Scholar]
- Kearney E. R., Walunas T. L., Karr R. W., Morton P. A., Loh D. Y., Bluestone J. A., Jenkins M. K. Antigen-dependent clonal expansion of a trace population of antigen-specific CD4+ T cells in vivo is dependent on CD28 costimulation and inhibited by CTLA-4. J Immunol. 1995 Aug 1;155(3):1032–1036. [PubMed] [Google Scholar]
- Kelsoe G. Life and death in germinal centers (redux). Immunity. 1996 Feb;4(2):107–111. doi: 10.1016/s1074-7613(00)80675-5. [DOI] [PubMed] [Google Scholar]
- Krummel M. F., Allison J. P. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995 Aug 1;182(2):459–465. doi: 10.1084/jem.182.2.459. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kuiper H. M., Brouwer M., Linsley P. S., van Lier R. A. Activated T cells can induce high levels of CTLA-4 expression on B cells. J Immunol. 1995 Aug 15;155(4):1776–1783. [PubMed] [Google Scholar]
- Lane P., Burdet C., Hubele S., Scheidegger D., Müller U., McConnell F., Kosco-Vilbois M. B cell function in mice transgenic for mCTLA4-H gamma 1: lack of germinal centers correlated with poor affinity maturation and class switching despite normal priming of CD4+ T cells. J Exp Med. 1994 Mar 1;179(3):819–830. doi: 10.1084/jem.179.3.819. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Leach D. R., Krummel M. F., Allison J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996 Mar 22;271(5256):1734–1736. doi: 10.1126/science.271.5256.1734. [DOI] [PubMed] [Google Scholar]
- 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]
- Linsley P. S. Distinct roles for CD28 and cytotoxic T lymphocyte-associated molecule-4 receptors during T cell activation? J Exp Med. 1995 Aug 1;182(2):289–292. doi: 10.1084/jem.182.2.289. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Linsley P. S., Greene J. L., Brady W., Bajorath J., Ledbetter J. A., Peach R. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity. 1994 Dec;1(9):793–801. doi: 10.1016/s1074-7613(94)80021-9. [DOI] [PubMed] [Google Scholar]
- Linsley P. S., Greene J. L., Tan P., Bradshaw J., Ledbetter J. A., Anasetti C., Damle N. K. Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J Exp Med. 1992 Dec 1;176(6):1595–1604. doi: 10.1084/jem.176.6.1595. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mueller D. L., Jenkins M. K., Schwartz R. H. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445–480. doi: 10.1146/annurev.iy.07.040189.002305. [DOI] [PubMed] [Google Scholar]
- Peach R. J., Bajorath J., Brady W., Leytze G., Greene J., Naemura J., Linsley P. S. Complementarity determining region 1 (CDR1)- and CDR3-analogous regions in CTLA-4 and CD28 determine the binding to B7-1. J Exp Med. 1994 Dec 1;180(6):2049–2058. doi: 10.1084/jem.180.6.2049. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Poppema S., Visser L., De Leij L. Reactivity of presumed anti-natural killer cell antibody Leu 7 with intrafollicular T lymphocytes. Clin Exp Immunol. 1983 Dec;54(3):834–837. [PMC free article] [PubMed] [Google Scholar]
- Sayegh M. H., Akalin E., Hancock W. W., Russell M. E., Carpenter C. B., Linsley P. S., Turka L. A. CD28-B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2. J Exp Med. 1995 May 1;181(5):1869–1874. doi: 10.1084/jem.181.5.1869. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tivol E. A., Borriello F., Schweitzer A. N., Lynch W. P., Bluestone J. A., Sharpe A. H. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995 Nov;3(5):541–547. doi: 10.1016/1074-7613(95)90125-6. [DOI] [PubMed] [Google Scholar]
- Velardi A., Mingari M. C., Moretta L., Grossi C. E. Functional analysis of cloned germinal center CD4+ cells with natural killer cell-related features. Divergence from typical T helper cells. J Immunol. 1986 Nov 1;137(9):2808–2813. [PubMed] [Google Scholar]
- Verwilghen J., Lovis R., De Boer M., Linsley P. S., Haines G. K., Koch A. E., Pope R. M. Expression of functional B7 and CTLA4 on rheumatoid synovial T cells. J Immunol. 1994 Aug 1;153(3):1378–1385. [PubMed] [Google Scholar]
- Vyth-Dreese F. A., Dellemijn T. A., Majoor D., de Jong D. Localization in situ of the co-stimulatory molecules B7.1, B7.2, CD40 and their ligands in normal human lymphoid tissue. Eur J Immunol. 1995 Nov;25(11):3023–3029. doi: 10.1002/eji.1830251106. [DOI] [PubMed] [Google Scholar]
- Walunas T. L., Lenschow D. J., Bakker C. Y., Linsley P. S., Freeman G. J., Green J. M., Thompson C. B., Bluestone J. A. CTLA-4 can function as a negative regulator of T cell activation. Immunity. 1994 Aug;1(5):405–413. doi: 10.1016/1074-7613(94)90071-x. [DOI] [PubMed] [Google Scholar]
- Waterhouse P., Penninger J. M., Timms E., Wakeham A., Shahinian A., Lee K. P., Thompson C. B., Griesser H., Mak T. W. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995 Nov 10;270(5238):985–988. doi: 10.1126/science.270.5238.985. [DOI] [PubMed] [Google Scholar]



