Abstract
CD3 signal transducing proteins are thought to be expressed on the surface of T cells only as part of clonotypic T cell receptor (TCR) complexes. Contrary to this paradigm, the present study describes surface expression of CD3 proteins independently of clonotypic TCR complexes, but only on immature thymocytes. Such novel clonotype- independent CD3 (CIC) complexes are composed primarily of CD3 gamma epsilon and secondarily of CD3 delta epsilon heterodimers that are independent of one another and are expressed on the cell surface in association with an unknown 90-100 kD protein termed CD3-associated protein (CD3AP). CIC complexes are expressed in normal mice on early thymocytes through the CD4+CD8+ stage of development, but not on mature peripheral T cells. Furthermore, CIC complexes are expressed by both TCR- severe combined immunodeficiency (SCID) thymocytes and thymoma cell lines, in the absence of any clonotypic chains. The isolation and biochemical characterization of surface CIC complexes provides a structural basis for the signaling effects of anti-CD3 epsilon antibody treatment in early thymocyte development.
Full Text
The Full Text of this article is available as a PDF (1.3 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Becker M. L., Near R., Mudgett-Hunter M., Margolies M. N., Kubo R. T., Kaye J., Hedrick S. M. Expression of a hybrid immunoglobulin-T cell receptor protein in transgenic mice. Cell. 1989 Sep 8;58(5):911–921. doi: 10.1016/0092-8674(89)90943-4. [DOI] [PubMed] [Google Scholar]
- Bonifacino J. S., Chen C., Lippincott-Schwartz J., Ashwell J. D., Klausner R. D. Subunit interactions within the T-cell antigen receptor: clues from the study of partial complexes. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6929–6933. doi: 10.1073/pnas.85.18.6929. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Born W., Miles C., White J., O'Brien R., Freed J. H., Marrack P., Kappler J., Kubo R. T. Peptide sequences of T-cell receptor delta and gamma chains are identical to predicted X and gamma proteins. Nature. 1987 Dec 10;330(6148):572–574. doi: 10.1038/330572a0. [DOI] [PubMed] [Google Scholar]
- Bosma G. C., Custer R. P., Bosma M. J. A severe combined immunodeficiency mutation in the mouse. Nature. 1983 Feb 10;301(5900):527–530. doi: 10.1038/301527a0. [DOI] [PubMed] [Google Scholar]
- Coulie P. G., Uyttenhove C., Wauters P., Manolios N., Klausner R. D., Samelson L. E., Van Snick J. Identification of a murine monoclonal antibody specific for an allotypic determinant on mouse CD3. Eur J Immunol. 1991 Jul;21(7):1703–1709. doi: 10.1002/eji.1830210718. [DOI] [PubMed] [Google Scholar]
- Fowlkes B. J., Pardoll D. M. Molecular and cellular events of T cell development. Adv Immunol. 1989;44:207–264. doi: 10.1016/s0065-2776(08)60643-4. [DOI] [PubMed] [Google Scholar]
- Goodman T., Lefrancois L. Intraepithelial lymphocytes. Anatomical site, not T cell receptor form, dictates phenotype and function. J Exp Med. 1989 Nov 1;170(5):1569–1581. doi: 10.1084/jem.170.5.1569. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Groettrup M., Ungewiss K., Azogui O., Palacios R., Owen M. J., Hayday A. C., von Boehmer H. A novel disulfide-linked heterodimer on pre-T cells consists of the T cell receptor beta chain and a 33 kd glycoprotein. Cell. 1993 Oct 22;75(2):283–294. doi: 10.1016/0092-8674(93)80070-u. [DOI] [PubMed] [Google Scholar]
- Habu S., Kimura M., Katsuki M., Hioki K., Nomura T. Correlation of T cell receptor gene rearrangements to T cell surface antigen expression and to serum immunoglobulin level in scid mice. Eur J Immunol. 1987 Oct;17(10):1467–1471. doi: 10.1002/eji.1830171013. [DOI] [PubMed] [Google Scholar]
- Jacobs H., Vandeputte D., Tolkamp L., de Vries E., Borst J., Berns A. CD3 components at the surface of pro-T cells can mediate pre-T cell development in vivo. Eur J Immunol. 1994 Apr;24(4):934–939. doi: 10.1002/eji.1830240423. [DOI] [PubMed] [Google Scholar]
- Kearse K. P., Wiest D. L., Singer A. Subcellular localization of T-cell receptor complexes containing tyrosine-phosphorylated zeta proteins in immature CD4+CD8+ thymocytes. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2438–2442. doi: 10.1073/pnas.90.6.2438. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Khorana H. G. Rhodopsin, photoreceptor of the rod cell. An emerging pattern for structure and function. J Biol Chem. 1992 Jan 5;267(1):1–4. [PubMed] [Google Scholar]
- Klausner R. D., Lippincott-Schwartz J., Bonifacino J. S. The T cell antigen receptor: insights into organelle biology. Annu Rev Cell Biol. 1990;6:403–431. doi: 10.1146/annurev.cb.06.110190.002155. [DOI] [PubMed] [Google Scholar]
- Kornfeld R., Kornfeld S. Assembly of asparagine-linked oligosaccharides. Annu Rev Biochem. 1985;54:631–664. doi: 10.1146/annurev.bi.54.070185.003215. [DOI] [PubMed] [Google Scholar]
- Kubo R. T., Born W., Kappler J. W., Marrack P., Pigeon M. Characterization of a monoclonal antibody which detects all murine alpha beta T cell receptors. J Immunol. 1989 Apr 15;142(8):2736–2742. [PubMed] [Google Scholar]
- Leo O., Foo M., Sachs D. H., Samelson L. E., Bluestone J. A. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1374–1378. doi: 10.1073/pnas.84.5.1374. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Levelt C. N., Ehrfeld A., Eichmann K. Regulation of thymocyte development through CD3. I. Timepoint of ligation of CD3 epsilon determines clonal deletion or induction of developmental program. J Exp Med. 1993 Mar 1;177(3):707–716. doi: 10.1084/jem.177.3.707. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Levelt C. N., Mombaerts P., Iglesias A., Tonegawa S., Eichmann K. Restoration of early thymocyte differentiation in T-cell receptor beta-chain-deficient mutant mice by transmembrane signaling through CD3 epsilon. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11401–11405. doi: 10.1073/pnas.90.23.11401. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ley S. C., Tan K. N., Kubo R., Sy M. S., Terhorst C. Surface expression of CD3 in the absence of T cell receptor (TcR): evidence for sorting of partial TcR/CD3 complexes in a post-endoplasmic reticulum compartment. Eur J Immunol. 1989 Dec;19(12):2309–2317. doi: 10.1002/eji.1830191220. [DOI] [PubMed] [Google Scholar]
- Mombaerts P., Clarke A. R., Rudnicki M. A., Iacomini J., Itohara S., Lafaille J. J., Wang L., Ichikawa Y., Jaenisch R., Hooper M. L. Mutations in T-cell antigen receptor genes alpha and beta block thymocyte development at different stages. Nature. 1992 Nov 19;360(6401):225–231. doi: 10.1038/360225a0. [DOI] [PubMed] [Google Scholar]
- Nakayama T., Singer A., Hsi E. D., Samelson L. E. Intrathymic signalling in immature CD4+CD8+ thymocytes results in tyrosine phosphorylation of the T-cell receptor zeta chain. Nature. 1989 Oct 19;341(6243):651–654. doi: 10.1038/341651a0. [DOI] [PubMed] [Google Scholar]
- O'Farrell P. Z., Goodman H. M., O'Farrell P. H. High resolution two-dimensional electrophoresis of basic as well as acidic proteins. Cell. 1977 Dec;12(4):1133–1141. doi: 10.1016/0092-8674(77)90176-3. [DOI] [PubMed] [Google Scholar]
- Orloff D. G., Frank S. J., Robey F. A., Weissman A. M., Klausner R. D. Biochemical characterization of the eta chain of the T-cell receptor. A unique subunit related to zeta. J Biol Chem. 1989 Sep 5;264(25):14812–14817. [PubMed] [Google Scholar]
- Samelson L. E., Germain R. N., Schwartz R. H. Monoclonal antibodies against the antigen receptor on a cloned T-cell hybrid. Proc Natl Acad Sci U S A. 1983 Nov;80(22):6972–6976. doi: 10.1073/pnas.80.22.6972. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Samelson L. E., Harford J. B., Klausner R. D. Identification of the components of the murine T cell antigen receptor complex. Cell. 1985 Nov;43(1):223–231. doi: 10.1016/0092-8674(85)90027-3. [DOI] [PubMed] [Google Scholar]
- Samelson L. E., Weissman A. M., Robey F. A., Berkower I., Klausner R. D. Characterization of an anti-peptide antibody that recognizes the murine analogue of the human T cell antigen receptor-T3 delta-chain. J Immunol. 1986 Nov 15;137(10):3254–3258. [PubMed] [Google Scholar]
- Shinkai Y., Koyasu S., Nakayama K., Murphy K. M., Loh D. Y., Reinherz E. L., Alt F. W. Restoration of T cell development in RAG-2-deficient mice by functional TCR transgenes. Science. 1993 Feb 5;259(5096):822–825. doi: 10.1126/science.8430336. [DOI] [PubMed] [Google Scholar]
- Shores E. W., Nakayama T., Wiest D. L., Takahama Y., Sharrow S., Singer A. Structurally distinct T cell receptor complexes on developmentally distinct T cell populations in severe combined immunodeficiency mice expressing a TCR beta transgene. J Immunol. 1993 Feb 15;150(4):1263–1275. [PubMed] [Google Scholar]
- Shores E. W., Van Ewijk W., Singer A. Disorganization and restoration of thymic medullary epithelial cells in T cell receptor-negative scid mice: evidence that receptor-bearing lymphocytes influence maturation of the thymic microenvironment. Eur J Immunol. 1991 Jul;21(7):1657–1661. doi: 10.1002/eji.1830210711. [DOI] [PubMed] [Google Scholar]
- Thompson J. A., Lau A. L., Cunningham D. D. Selective radiolabeling of cell surface proteins to a high specific activity. Biochemistry. 1987 Feb 10;26(3):743–750. doi: 10.1021/bi00377a014. [DOI] [PubMed] [Google Scholar]
- Wegener A. M., Letourneur F., Hoeveler A., Brocker T., Luton F., Malissen B. The T cell receptor/CD3 complex is composed of at least two autonomous transduction modules. Cell. 1992 Jan 10;68(1):83–95. doi: 10.1016/0092-8674(92)90208-t. [DOI] [PubMed] [Google Scholar]
- Wiest D. L., Yuan L., Jefferson J., Benveniste P., Tsokos M., Klausner R. D., Glimcher L. H., Samelson L. E., Singer A. Regulation of T cell receptor expression in immature CD4+CD8+ thymocytes by p56lck tyrosine kinase: basis for differential signaling by CD4 and CD8 in immature thymocytes expressing both coreceptor molecules. J Exp Med. 1993 Nov 1;178(5):1701–1712. doi: 10.1084/jem.178.5.1701. [DOI] [PMC free article] [PubMed] [Google Scholar]