Abstract
The CD4-8- thymocyte subset contains immature precursors for phenotypically and functionally mature CD4+8- and CD4-8+ thymocytes and peripheral T cells, as well as nonmature CD4+8+ thymocytes, most of which die in situ. The intrathymic death of most thymocytes is probably related to selective influences that ensure that only those precursors bearing self-major histocompatibility complex (MHC)-restricted and self-tolerant T-cell antigen receptors (TCR) survive to complete the maturation process. Interactions between surface molecules on thymocytes (TCR, CD4, and CD8) and thymic stromal cells (MHC proteins) are critical to repertoire selection. To understand this process, the lineage relationships among immature, nonmature, and mature thymocytes must be defined. We have examined directly the precursor-progeny relationships among CD4+8-, CD4-8+, and CD4+8+ murine thymocyte subsets by assessing their short-term (less than 5 days) developmental potentials following intrathymic injection into Thy-1 congenic, unirradiated host mice. Our results identify TCR-/lo CD4-8+ and TCRlo CD4+8+ blast cells as sequential intermediates in the development of mature TCRhi CD4+8- and TCRhi CD4-8+ thymocytes from CD4-8- precursors, thus defining at least one intrathymic maturation pathway for T lymphocytes.
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Selected References
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- Adkins B., Mueller C., Okada C. Y., Reichert R. A., Weissman I. L., Spangrude G. J. Early events in T-cell maturation. Annu Rev Immunol. 1987;5:325–365. doi: 10.1146/annurev.iy.05.040187.001545. [DOI] [PubMed] [Google Scholar]
- Amagai T., Kina T., Hirokawa K., Nishikawa S., Imanishi J., Katsura Y. Dysfunction of irradiated thymus for the development of helper T cells. J Immunol. 1987 Jul 15;139(2):358–364. [PubMed] [Google Scholar]
- Cantor H., Weissman I. Development and function of subpopulations of thymocytes and T lymphocytes. Prog Allergy. 1976;20:1–64. [PubMed] [Google Scholar]
- Crispe I. N., Bevan M. J. Expression and functional significance of the J11d marker on mouse thymocytes. J Immunol. 1987 Apr 1;138(7):2013–2018. [PubMed] [Google Scholar]
- Crispe I. N., Moore M. W., Husmann L. A., Smith L., Bevan M. J., Shimonkevitz R. P. Differentiation potential of subsets of CD4-8- thymocytes. Nature. 1987 Sep 24;329(6137):336–339. doi: 10.1038/329336a0. [DOI] [PubMed] [Google Scholar]
- Fink P. J., Bevan M. J. H-2 antigens of the thymus determine lymphocyte specificity. J Exp Med. 1978 Sep 1;148(3):766–775. doi: 10.1084/jem.148.3.766. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fowlkes B. J., Kruisbeek A. M., Ton-That H., Weston M. A., Coligan J. E., Schwartz R. H., Pardoll D. M. A novel population of T-cell receptor alpha beta-bearing thymocytes which predominantly expresses a single V beta gene family. Nature. 1987 Sep 17;329(6136):251–254. doi: 10.1038/329251a0. [DOI] [PubMed] [Google Scholar]
- Fowlkes B. J., Schwartz R. H., Pardoll D. M. Deletion of self-reactive thymocytes occurs at a CD4+8+ precursor stage. Nature. 1988 Aug 18;334(6183):620–623. doi: 10.1038/334620a0. [DOI] [PubMed] [Google Scholar]
- Guidos C. J., Weissman I. L., Adkins B. Developmental potential of CD4-8- thymocytes. Peripheral progeny include mature CD4-8- T cells bearing alpha beta T cell receptor. J Immunol. 1989 Jun 1;142(11):3773–3780. [PubMed] [Google Scholar]
- Havran W. L., Poenie M., Kimura J., Tsien R., Weiss A., Allison J. P. Expression and function of the CD3-antigen receptor on murine CD4+8+ thymocytes. Nature. 1987 Nov 12;330(6144):170–173. doi: 10.1038/330170a0. [DOI] [PubMed] [Google Scholar]
- Hünig T. Cross-linking of the T cell antigen receptor interferes with the generation of CD4+8+ thymocytes from their immediate CD4-8+ precursors. Eur J Immunol. 1988 Dec;18(12):2089–2092. doi: 10.1002/eji.1830181234. [DOI] [PubMed] [Google Scholar]
- Kappler J. W., Wade T., White J., Kushnir E., Blackman M., Bill J., Roehm N., Marrack P. A T cell receptor V beta segment that imparts reactivity to a class II major histocompatibility complex product. Cell. 1987 Apr 24;49(2):263–271. doi: 10.1016/0092-8674(87)90567-8. [DOI] [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]
- Kruisbeek A. M., Fultz M. J., Sharrow S. O., Singer A., Mond J. J. Early development of the T cell repertoire. In vivo treatment of neonatal mice with anti-Ia antibodies interferes with differentiation of I-restricted T cells but not K/D-restricted T cells. J Exp Med. 1983 Jun 1;157(6):1932–1946. doi: 10.1084/jem.157.6.1932. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lanier L. L., Allison J. P., Phillips J. H. Correlation of cell surface antigen expression on human thymocytes by multi-color flow cytometric analysis: implications for differentiation. J Immunol. 1986 Oct 15;137(8):2501–2507. [PubMed] [Google Scholar]
- MacDonald H. R., Budd R. C., Howe R. C. A CD3- subset of CD4-8+ thymocytes: a rapidly cycling intermediate in the generation of CD4+8+ cells. Eur J Immunol. 1988 Apr;18(4):519–523. doi: 10.1002/eji.1830180405. [DOI] [PubMed] [Google Scholar]
- MacDonald H. R., Hengartner H., Pedrazzini T. Intrathymic deletion of self-reactive cells prevented by neonatal anti-CD4 antibody treatment. Nature. 1988 Sep 8;335(6186):174–176. doi: 10.1038/335174a0. [DOI] [PubMed] [Google Scholar]
- MacDonald H. R., Lees R. K., Schneider R., Zinkernagel R. M., Hengartner H. Positive selection of CD4+ thymocytes controlled by MHC class II gene products. Nature. 1988 Dec 1;336(6198):471–473. doi: 10.1038/336471a0. [DOI] [PubMed] [Google Scholar]
- Marrack P., Kappler J. The T cell receptor. Science. 1987 Nov 20;238(4830):1073–1079. doi: 10.1126/science.3317824. [DOI] [PubMed] [Google Scholar]
- Maruŝić-Galesić S., Stephany D. A., Longo D. L., Kruisbeek A. M. Development of CD4-CD8+ cytotoxic T cells requires interactions with class I MHC determinants. Nature. 1988 May 12;333(6169):180–183. doi: 10.1038/333180a0. [DOI] [PubMed] [Google Scholar]
- McCarthy S. A., Kruisbeek A. M., Uppenkamp I. K., Sharrow S. O., Singer A. Engagement of the CD4 molecule influences cell surface expression of the T-cell receptor on thymocytes. Nature. 1988 Nov 3;336(6194):76–79. doi: 10.1038/336076a0. [DOI] [PubMed] [Google Scholar]
- McDuffie M., Born W., Marrack P., Kappler J. The role of the T-cell receptor in thymocyte maturation: effects in vivo of anti-receptor antibody. Proc Natl Acad Sci U S A. 1986 Nov;83(22):8728–8732. doi: 10.1073/pnas.83.22.8728. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McPhee D., Pye J., Shortman K. The differentiation of T lymphocytes. V. Evidence for intrathymic death of most thymocytes. Thymus. 1979 Nov;1(3):151–162. [PubMed] [Google Scholar]
- Nikolić-Zugić J., Bevan M. J. Thymocytes expressing CD8 differentiate into CD4+ cells following intrathymic injection. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8633–8637. doi: 10.1073/pnas.85.22.8633. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Paterson D. J., Williams A. F. An intermediate cell in thymocyte differentiation that expresses CD8 but not CD4 antigen. J Exp Med. 1987 Nov 1;166(5):1603–1608. doi: 10.1084/jem.166.5.1603. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Roehm N., Herron L., Cambier J., DiGuisto D., Haskins K., Kappler J., Marrack P. The major histocompatibility complex-restricted antigen receptor on T cells: distribution on thymus and peripheral T cells. Cell. 1984 Sep;38(2):577–584. doi: 10.1016/0092-8674(84)90512-9. [DOI] [PubMed] [Google Scholar]
- Scollay R. G., Butcher E. C., Weissman I. L. Thymus cell migration. Quantitative aspects of cellular traffic from the thymus to the periphery in mice. Eur J Immunol. 1980 Mar;10(3):210–218. doi: 10.1002/eji.1830100310. [DOI] [PubMed] [Google Scholar]
- 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]
- Shortman K., Wilson A., Egerton M., Pearse M., Scollay R. Immature CD4- CD8+ murine thymocytes. Cell Immunol. 1988 May;113(2):462–479. doi: 10.1016/0008-8749(88)90042-1. [DOI] [PubMed] [Google Scholar]
- Smith L. CD4+ murine T cells develop from CD8+ precursors in vivo. Nature. 1987 Apr 23;326(6115):798–800. doi: 10.1038/326798a0. [DOI] [PubMed] [Google Scholar]
- Spangrude G. J., Heimfeld S., Weissman I. L. Purification and characterization of mouse hematopoietic stem cells. Science. 1988 Jul 1;241(4861):58–62. doi: 10.1126/science.2898810. [DOI] [PubMed] [Google Scholar]
- Spangrude G. J., Muller-Sieburg C. E., Heimfeld S., Weissman I. L. Two rare populations of mouse Thy-1lo bone marrow cells repopulate the thymus. J Exp Med. 1988 May 1;167(5):1671–1683. doi: 10.1084/jem.167.5.1671. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weissman I. L., Small M., Fathman C. G., Herzenberg L. A. Differentiation of thymus cells-1,2. Fed Proc. 1975 Feb;34(2):141–144. [PubMed] [Google Scholar]
- Weissman I. L. Thymus cell migration. J Exp Med. 1967 Aug 1;126(2):291–304. doi: 10.1084/jem.126.2.291. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zinkernagel R. M., Callahan G. N., Althage A., Cooper S., Klein P. A., Klein J. On the thymus in the differentiation of "H-2 self-recognition" by T cells: evidence for dual recognition? J Exp Med. 1978 Mar 1;147(3):882–896. doi: 10.1084/jem.147.3.882. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zuñiga-Pflucker J. C., Longo D. L., Kruisbeek A. M. Positive selection of CD4-CD8+ T cells in the thymus of normal mice. Nature. 1989 Mar 2;338(6210):76–78. doi: 10.1038/338076a0. [DOI] [PubMed] [Google Scholar]
- von Boehmer H. The developmental biology of T lymphocytes. Annu Rev Immunol. 1988;6:309–326. doi: 10.1146/annurev.iy.06.040188.001521. [DOI] [PubMed] [Google Scholar]