Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1995 May 1;181(5):1623–1633. doi: 10.1084/jem.181.5.1623

Stochastic coreceptor shut-off is restricted to the CD4 lineage maturation pathway

PMCID: PMC2191984  PMID: 7722442

Abstract

Kinetics of mature T cell generation in the thymus of normal or major histocompatibility complex (MHC) class I- or II-deficient mice were studied by the bromodeoxyuridine pulse labeling method. As previously described, the early activation and final maturation phases were found to be synchronous for the two T cell lineages, but CD4+8- cells were generated faster than CD4-8+ cells in MHC class I- and II-deficient mice, respectively. CD8 downregulation started on day 2 after cell proliferation even in the absence of MHC class II expression. CD8 downregulation thus appears to be stochastic at its beginning. By contrast, CD4 shut-off was found totally instructive, as the generation of CD4lo8+ cells with a high TCR density was not observed in class I- deficient mice. The analysis of the V beta 14 TCR frequencies in CD4/8 subsets in normal and MHC-deficient mice confirmed that CD4 and CD8 generation pathways are not symmetrical. These findings show that commitment towards the CD4+8- or CD4-8+ phenotype is controlled at the CD8lo step for the former and at the CD4+8+ double-positive stage for the latter.

Full Text

The Full Text of this article is available as a PDF (935.5 KB).

Selected References

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

  1. Acha-Orbea H., Zinkernagel R. M., Hengartner H. Cytotoxic T cell clone-specific monoclonal antibodies used to select clonotypic antigen-specific cytotoxic T cells. Eur J Immunol. 1985 Jan;15(1):31–36. doi: 10.1002/eji.1830150107. [DOI] [PubMed] [Google Scholar]
  2. Arpaia E., Shahar M., Dadi H., Cohen A., Roifman C. M. Defective T cell receptor signaling and CD8+ thymic selection in humans lacking zap-70 kinase. Cell. 1994 Mar 11;76(5):947–958. doi: 10.1016/0092-8674(94)90368-9. [DOI] [PubMed] [Google Scholar]
  3. Ashton-Rickardt P. G., Bandeira A., Delaney J. R., Van Kaer L., Pircher H. P., Zinkernagel R. M., Tonegawa S. Evidence for a differential avidity model of T cell selection in the thymus. Cell. 1994 Feb 25;76(4):651–663. doi: 10.1016/0092-8674(94)90505-3. [DOI] [PubMed] [Google Scholar]
  4. Baron A., Hafen K., von Boehmer H. A human CD4 transgene rescues CD4-CD8+ cells in beta 2-microglobulin-deficient mice. Eur J Immunol. 1994 Aug;24(8):1933–1936. doi: 10.1002/eji.1830240834. [DOI] [PubMed] [Google Scholar]
  5. Bendelac A., Schwartz R. H. CD4+ and CD8+ T cells acquire specific lymphokine secretion potentials during thymic maturation. Nature. 1991 Sep 5;353(6339):68–71. doi: 10.1038/353068a0. [DOI] [PubMed] [Google Scholar]
  6. Borgulya P., Kishi H., Müller U., Kirberg J., von Boehmer H. Development of the CD4 and CD8 lineage of T cells: instruction versus selection. EMBO J. 1991 Apr;10(4):913–918. doi: 10.1002/j.1460-2075.1991.tb08024.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bruce J., Symington F. W., McKearn T. J., Sprent J. A monoclonal antibody discriminating between subsets of T and B cells. J Immunol. 1981 Dec;127(6):2496–2501. [PubMed] [Google Scholar]
  8. Ceredig R., Dialynas D. P., Fitch F. W., MacDonald H. R. Precursors of T cell growth factor producing cells in the thymus: ontogeny, frequency, and quantitative recovery in a subpopulation of phenotypically mature thymocytes defined by monoclonal antibody GK-1.5. J Exp Med. 1983 Nov 1;158(5):1654–1671. doi: 10.1084/jem.158.5.1654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chan S. H., Cosgrove D., Waltzinger C., Benoist C., Mathis D. Another view of the selective model of thymocyte selection. Cell. 1993 Apr 23;73(2):225–236. doi: 10.1016/0092-8674(93)90225-f. [DOI] [PubMed] [Google Scholar]
  10. Corbella P., Moskophidis D., Spanopoulou E., Mamalaki C., Tolaini M., Itano A., Lans D., Baltimore D., Robey E., Kioussis D. Functional commitment to helper T cell lineage precedes positive selection and is independent of T cell receptor MHC specificity. Immunity. 1994 Jul;1(4):269–276. doi: 10.1016/1074-7613(94)90078-7. [DOI] [PubMed] [Google Scholar]
  11. Cosgrove D., Gray D., Dierich A., Kaufman J., Lemeur M., Benoist C., Mathis D. Mice lacking MHC class II molecules. Cell. 1991 Sep 6;66(5):1051–1066. doi: 10.1016/0092-8674(91)90448-8. [DOI] [PubMed] [Google Scholar]
  12. Crooks M. E., Littman D. R. Disruption of T lymphocyte positive and negative selection in mice lacking the CD8 beta chain. Immunity. 1994 Jul;1(4):277–285. doi: 10.1016/1074-7613(94)90079-5. [DOI] [PubMed] [Google Scholar]
  13. Crump A. L., Grusby M. J., Glimcher L. H., Cantor H. Thymocyte development in major histocompatibility complex-deficient mice: evidence for stochastic commitment to the CD4 and CD8 lineages. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10739–10743. doi: 10.1073/pnas.90.22.10739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Davis C. B., Killeen N., Crooks M. E., Raulet D., Littman D. R. Evidence for a stochastic mechanism in the differentiation of mature subsets of T lymphocytes. Cell. 1993 Apr 23;73(2):237–247. doi: 10.1016/0092-8674(93)90226-g. [DOI] [PubMed] [Google Scholar]
  15. Dialynas D. P., Wilde D. B., Marrack P., Pierres A., Wall K. A., Havran W., Otten G., Loken M. R., Pierres M., Kappler J. Characterization of the murine antigenic determinant, designated L3T4a, recognized by monoclonal antibody GK1.5: expression of L3T4a by functional T cell clones appears to correlate primarily with class II MHC antigen-reactivity. Immunol Rev. 1983;74:29–56. doi: 10.1111/j.1600-065x.1983.tb01083.x. [DOI] [PubMed] [Google Scholar]
  16. Fung-Leung W. P., Kündig T. M., Ngo K., Panakos J., De Sousa-Hitzler J., Wang E., Ohashi P. S., Mak T. W., Lau C. Y. Reduced thymic maturation but normal effector function of CD8+ T cells in CD8 beta gene-targeted mice. J Exp Med. 1994 Sep 1;180(3):959–967. doi: 10.1084/jem.180.3.959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fung-Leung W. P., Louie M. C., Limmer A., Ohashi P. S., Ngo K., Chen L., Kawai K., Lacy E., Loh D. Y., Mak T. W. The lack of CD8 alpha cytoplasmic domain resulted in a dramatic decrease in efficiency in thymic maturation but only a moderate reduction in cytotoxic function of CD8+ T lymphocytes. Eur J Immunol. 1993 Nov;23(11):2834–2840. doi: 10.1002/eji.1830231117. [DOI] [PubMed] [Google Scholar]
  18. Fung-Leung W. P., Schilham M. W., Rahemtulla A., Kündig T. M., Vollenweider M., Potter J., van Ewijk W., Mak T. W. CD8 is needed for development of cytotoxic T cells but not helper T cells. Cell. 1991 May 3;65(3):443–449. doi: 10.1016/0092-8674(91)90462-8. [DOI] [PubMed] [Google Scholar]
  19. Hogquist K. A., Jameson S. C., Heath W. R., Howard J. L., Bevan M. J., Carbone F. R. T cell receptor antagonist peptides induce positive selection. Cell. 1994 Jan 14;76(1):17–27. doi: 10.1016/0092-8674(94)90169-4. [DOI] [PubMed] [Google Scholar]
  20. Itano A., Cado D., Chan F. K., Robey E. A role for the cytoplasmic tail of the beta chain of CD8 in thymic selection. Immunity. 1994 Jul;1(4):287–290. doi: 10.1016/1074-7613(94)90080-9. [DOI] [PubMed] [Google Scholar]
  21. Itano A., Kioussis D., Robey E. Stochastic component to development of class I major histocompatibility complex-specific T cells. Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):220–224. doi: 10.1073/pnas.91.1.220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Koller B. H., Marrack P., Kappler J. W., Smithies O. Normal development of mice deficient in beta 2M, MHC class I proteins, and CD8+ T cells. Science. 1990 Jun 8;248(4960):1227–1230. doi: 10.1126/science.2112266. [DOI] [PubMed] [Google Scholar]
  23. Ledbetter J. A., Seaman W. E. The Lyt-2, Lyt-3 macromolecules: structural and functional studies. Immunol Rev. 1982;68:197–218. doi: 10.1111/j.1600-065x.1982.tb01065.x. [DOI] [PubMed] [Google Scholar]
  24. Liao N. S., Maltzman J., Raulet D. H. Positive selection determines T cell receptor V beta 14 gene usage by CD8+ T cells. J Exp Med. 1989 Jul 1;170(1):135–143. doi: 10.1084/jem.170.1.135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Linette G. P., Grusby M. J., Hedrick S. M., Hansen T. H., Glimcher L. H., Korsmeyer S. J. Bcl-2 is upregulated at the CD4+ CD8+ stage during positive selection and promotes thymocyte differentiation at several control points. Immunity. 1994 Jun;1(3):197–205. doi: 10.1016/1074-7613(94)90098-1. [DOI] [PubMed] [Google Scholar]
  26. Lucas B., Vasseur F., Penit C. Normal sequence of phenotypic transitions in one cohort of 5-bromo-2'-deoxyuridine-pulse-labeled thymocytes. Correlation with T cell receptor expression. J Immunol. 1993 Nov 1;151(9):4574–4582. [PubMed] [Google Scholar]
  27. Lucas B., Vasseur F., Penit C. Production, selection, and maturation of thymocytes with high surface density of TCR. J Immunol. 1994 Jul 1;153(1):53–62. [PubMed] [Google Scholar]
  28. Lundberg K., Shortman K. Small cortical thymocytes are subject to positive selection. J Exp Med. 1994 May 1;179(5):1475–1483. doi: 10.1084/jem.179.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Marodon G., Rocha B. Generation of mature T cell populations in the thymus: CD4 or CD8 down-regulation occurs at different stages of thymocyte differentiation. Eur J Immunol. 1994 Jan;24(1):196–204. doi: 10.1002/eji.1830240131. [DOI] [PubMed] [Google Scholar]
  30. Penit C., Vasseur F. Phenotype analysis of cycling and postcycling thymocytes: evaluation of detection methods for BrdUrd and surface proteins. Cytometry. 1993 Oct;14(7):757–763. doi: 10.1002/cyto.990140708. [DOI] [PubMed] [Google Scholar]
  31. Petrie H. T., Strasser A., Harris A. W., Hugo P., Shortman K. CD4+8- and CD4-8+ mature thymocytes require different post-selection processing for final development. J Immunol. 1993 Aug 1;151(3):1273–1279. [PubMed] [Google Scholar]
  32. Porstmann T., Ternynck T., Avrameas S. Quantitation of 5-bromo-2-deoxyuridine incorporation into DNA: an enzyme immunoassay for the assessment of the lymphoid cell proliferative response. J Immunol Methods. 1985 Sep 3;82(1):169–179. doi: 10.1016/0022-1759(85)90236-4. [DOI] [PubMed] [Google Scholar]
  33. Robey E. A., Fowlkes B. J., Gordon J. W., Kioussis D., von Boehmer H., Ramsdell F., Axel R. Thymic selection in CD8 transgenic mice supports an instructive model for commitment to a CD4 or CD8 lineage. Cell. 1991 Jan 11;64(1):99–107. doi: 10.1016/0092-8674(91)90212-h. [DOI] [PubMed] [Google Scholar]
  34. Robey E., Itano A., Fanslow W. C., Fowlkes B. J. Constitutive CD8 expression allows inefficient maturation of CD4+ helper T cells in class II major histocompatibility complex mutant mice. J Exp Med. 1994 Jun 1;179(6):1997–2004. doi: 10.1084/jem.179.6.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sebzda E., Wallace V. A., Mayer J., Yeung R. S., Mak T. W., Ohashi P. S. Positive and negative thymocyte selection induced by different concentrations of a single peptide. Science. 1994 Mar 18;263(5153):1615–1618. doi: 10.1126/science.8128249. [DOI] [PubMed] [Google Scholar]
  36. Seong R. H., Chamberlain J. W., Parnes J. R. Signal for T-cell differentiation to a CD4 cell lineage is delivered by CD4 transmembrane region and/or cytoplasmic tail. Nature. 1992 Apr 23;356(6371):718–720. doi: 10.1038/356718a0. [DOI] [PubMed] [Google Scholar]
  37. Staerz U. D., Bevan M. J. Activation of resting T lymphocytes by a monoclonal antibody directed against an allotypic determinant on the T cell receptor. Eur J Immunol. 1986 Mar;16(3):263–270. doi: 10.1002/eji.1830160310. [DOI] [PubMed] [Google Scholar]
  38. Swat W., Dessing M., Baron A., Kisielow P., von Boehmer H. Phenotypic changes accompanying positive selection of CD4+CD8+ thymocytes. Eur J Immunol. 1992 Sep;22(9):2367–2372. doi: 10.1002/eji.1830220928. [DOI] [PubMed] [Google Scholar]
  39. Takahama Y., Suzuki H., Katz K. S., Grusby M. J., Singer A. Positive selection of CD4+ T cells by TCR ligation without aggregation even in the absence of MHC. Nature. 1994 Sep 1;371(6492):67–70. doi: 10.1038/371067a0. [DOI] [PubMed] [Google Scholar]
  40. Teh H. S., Kisielow P., Scott B., Kishi H., Uematsu Y., Blüthmann H., von Boehmer H. Thymic major histocompatibility complex antigens and the alpha beta T-cell receptor determine the CD4/CD8 phenotype of T cells. Nature. 1988 Sep 15;335(6187):229–233. doi: 10.1038/335229a0. [DOI] [PubMed] [Google Scholar]
  41. Vicari A., de Moraes M. do C., Gombert J. M., Dy M., Penit C., Papiernik M., Herbelin A. Interleukin 7 induces preferential expansion of V beta 8.2+CD4-8- and V beta 8.2+CD4+8- murine thymocytes positively selected by class I molecules. J Exp Med. 1994 Aug 1;180(2):653–661. doi: 10.1084/jem.180.2.653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Yokoyama W. M., Koning F., Kehn P. J., Pereira G. M., Stingl G., Coligan J. E., Shevach E. M. Characterization of a cell surface-expressed disulfide-linked dimer involved in murine T cell activation. J Immunol. 1988 Jul 15;141(2):369–376. [PubMed] [Google Scholar]
  43. van Meerwijk J. P., Germain R. N. Development of mature CD8+ thymocytes: selection rather than instruction? Science. 1993 Aug 13;261(5123):911–915. doi: 10.1126/science.8102208. [DOI] [PubMed] [Google Scholar]

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

RESOURCES