Abstract
Thymic repertoire selection requires the expression of the alpha beta CD3 T-cell receptor (TCR) together with the coreceptors CD4 and CD8. The appearance of CD4 and CD8 on thymocytes is the hallmark of a complex maturation step, accompanied by downregulation of the interleukin 2 receptor (IL-2R) alpha chain, arrest of rearrangement (i.e., allelic exclusion) of the TCR beta-chain locus, a burst of cell divisions, and reduction in cell size. This maturation step is inhibited in TCR beta-chain-deficient mouse strains and may depend on surface expression of an immature TCR complex containing CD3 and TCR beta chains but no TCR alpha chain. Here we show that the CD4+8+ double-positive (DP) stage can be induced by treatment of fetal thymic organ cultures with anti-CD3 epsilon monoclonal antibodies in several TCR beta-chain-deficient mouse strains: severe combined immunodeficient (scid) mice, mice carrying a mutation in the recombination activating gene 1 (Rag-1), or mice carrying a deletion in the TCR beta-chain locus itself. These findings suggest that CD3 epsilon is expressed on the thymocyte surface independent of and prior to the TCR beta chain. The data are consistent with the notion that in wild-type mice the DP stage is induced by transmembrane signaling through an immature CD3-TCR beta-chain complex, which can be bypassed by crosslinking of CD3 epsilon alone.
Full text
PDF




Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Anderson S. J., Abraham K. M., Nakayama T., Singer A., Perlmutter R. M. Inhibition of T-cell receptor beta-chain gene rearrangement by overexpression of the non-receptor protein tyrosine kinase p56lck. EMBO J. 1992 Dec;11(13):4877–4886. doi: 10.1002/j.1460-2075.1992.tb05594.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bosma M. J., Carroll A. M. The SCID mouse mutant: definition, characterization, and potential uses. Annu Rev Immunol. 1991;9:323–350. doi: 10.1146/annurev.iy.09.040191.001543. [DOI] [PubMed] [Google Scholar]
- Carrel S., Mach J. P., Miescher G., Salvi S., Giuffrè L., Schreyer M., Isler P. Phorbol 12-myristate 13-acetate induces surface expression of T3 on human immature T cell lines with and without concomitant expression of the T cell antigen receptor complex. Eur J Immunol. 1987 Aug;17(8):1079–1087. doi: 10.1002/eji.1830170802. [DOI] [PubMed] [Google Scholar]
- Ceredig R., Lowenthal J. W., Nabholz M., MacDonald H. R. Expression of interleukin-2 receptors as a differentiation marker on intrathymic stem cells. Nature. 1985 Mar 7;314(6006):98–100. doi: 10.1038/314098a0. [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., Baron A., Griffiths G., Palacios R., von Boehmer H. T cell receptor (TCR) beta chain homodimers on the surface of immature but not mature alpha, gamma, delta chain deficient T cell lines. EMBO J. 1992 Jul;11(7):2735–2745. doi: 10.1002/j.1460-2075.1992.tb05339.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jenkinson E. J., Van Ewijk W., Owen J. J. Major histocompatibility complex antigen expression on the epithelium of the developing thymus in normal and nude mice. J Exp Med. 1981 Feb 1;153(2):280–292. doi: 10.1084/jem.153.2.280. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kisielow P., Blüthmann H., Staerz U. D., Steinmetz M., von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature. 1988 Jun 23;333(6175):742–746. doi: 10.1038/333742a0. [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]
- Levin S. D., Anderson S. J., Forbush K. A., Perlmutter R. M. A dominant-negative transgene defines a role for p56lck in thymopoiesis. EMBO J. 1993 Apr;12(4):1671–1680. doi: 10.1002/j.1460-2075.1993.tb05812.x. [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]
- Molina T. J., Kishihara K., Siderovski D. P., van Ewijk W., Narendran A., Timms E., Wakeham A., Paige C. J., Hartmann K. U., Veillette A. Profound block in thymocyte development in mice lacking p56lck. Nature. 1992 May 14;357(6374):161–164. doi: 10.1038/357161a0. [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]
- Mombaerts P., Iacomini J., Johnson R. S., Herrup K., Tonegawa S., Papaioannou V. E. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992 Mar 6;68(5):869–877. doi: 10.1016/0092-8674(92)90030-g. [DOI] [PubMed] [Google Scholar]
- Moreau J. L., Nabholz M., Diamantstein T., Malek T., Shevach E., Thèze J. Monoclonal antibodies identify three epitope clusters on the mouse p55 subunit of the interleukin 2 receptor: relationship to the interleukin 2-binding site. Eur J Immunol. 1987 Jul;17(7):929–935. doi: 10.1002/eji.1830170706. [DOI] [PubMed] [Google Scholar]
- Owen J. J., Owen M. J., Williams G. T., Kingston R., Jenkinson E. J. The effects of anti-CD3 antibodies on the development of T-cell receptor alpha beta + lymphocytes in embryonic thymus organ cultures. Immunology. 1988 Apr;63(4):639–642. [PMC free article] [PubMed] [Google Scholar]
- Pearse M., Wu L., Egerton M., Wilson A., Shortman K., Scollay R. A murine early thymocyte developmental sequence is marked by transient expression of the interleukin 2 receptor. Proc Natl Acad Sci U S A. 1989 Mar;86(5):1614–1618. doi: 10.1073/pnas.86.5.1614. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Petrie H. T., Pearse M., Scollay R., Shortman K. Development of immature thymocytes: initiation of CD3, CD4, and CD8 acquisition parallels down-regulation of the interleukin 2 receptor alpha chain. Eur J Immunol. 1990 Dec;20(12):2813–2815. doi: 10.1002/eji.1830201243. [DOI] [PubMed] [Google Scholar]
- Portoles P., Rojo J., Golby A., Bonneville M., Gromkowski S., Greenbaum L., Janeway C. A., Jr, Murphy D. B., Bottomly K. Monoclonal antibodies to murine CD3 epsilon define distinct epitopes, one of which may interact with CD4 during T cell activation. J Immunol. 1989 Jun 15;142(12):4169–4175. [PubMed] [Google Scholar]
- Punt J. A., Kubo R. T., Saito T., Finkel T. H., Kathiresan S., Blank K. J., Hashimoto Y. Surface expression of a T cell receptor beta (TCR-beta) chain in the absence of TCR-alpha, -delta, and -gamma proteins. J Exp Med. 1991 Oct 1;174(4):775–783. doi: 10.1084/jem.174.4.775. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Raulet D. H. Expression and function of interleukin-2 receptors on immature thymocytes. Nature. 1985 Mar 7;314(6006):101–103. doi: 10.1038/314101a0. [DOI] [PubMed] [Google Scholar]
- Scott B., Blüthmann H., Teh H. S., von Boehmer H. The generation of mature T cells requires interaction of the alpha beta T-cell receptor with major histocompatibility antigens. Nature. 1989 Apr 13;338(6216):591–593. doi: 10.1038/338591a0. [DOI] [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]
- Shinkai Y., Rathbun G., Lam K. P., Oltz E. M., Stewart V., Mendelsohn M., Charron J., Datta M., Young F., Stall A. M. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992 Mar 6;68(5):855–867. doi: 10.1016/0092-8674(92)90029-c. [DOI] [PubMed] [Google Scholar]
- Unkeless J. C. Characterization of a monoclonal antibody directed against mouse macrophage and lymphocyte Fc receptors. J Exp Med. 1979 Sep 19;150(3):580–596. doi: 10.1084/jem.150.3.580. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yachelini P., Falk I., Eichmann K. Deviations in thymocyte development induced by divalent and monovalent ligation of the alpha/beta T cell receptor and by its cross-linking to CD8. J Immunol. 1990 Sep 1;145(5):1382–1389. [PubMed] [Google Scholar]
- von Boehmer H. Developmental biology of T cells in T cell-receptor transgenic mice. Annu Rev Immunol. 1990;8:531–556. doi: 10.1146/annurev.iy.08.040190.002531. [DOI] [PubMed] [Google Scholar]