Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Nov 1;184(5):1619–1630. doi: 10.1084/jem.184.5.1619

Thymocytes can become mature T cells without passing through the CD4+ CD8+, double-positive stage

PMCID: PMC2192895  PMID: 8920852

Abstract

T cells bearing the class II-restricted, DO-T cell receptor (TCR) are CD4+ if their thymocyte precursors are positively selected on the class II protein, IAd, but they are almost all CD4- after positive selection on a class II for which they have higher avidity, IAb. DO-TCR+ T cells mature in H-2b mice lacking CD4. CD4- DO-TCR+ T cells appear in H-2b mice at the same rate as their CD4+ counterparts appear in H-2d animals, suggesting that the CD4- cells are not the product of some minor pathway of thymocyte development and selection. In H-2b CD4 knock out mice expressing human CD2 under the control of the mouse CD4 promoter, mature DO-TCR+ cells did not express human CD2. These results suggest that the CD4-CD8-, DO-TCR+ mature T cells have developed without ever passing through the equivalent of a CD4+,CD8+ stage. The early expression of alpha/beta receptors (TCRs) on thymocytes in TCR transgenic mice may allow maturation of this type. Passage through the equivalent of the CD4+ CD8+, double-positive stage is not essential for differentiation of thymocytes into mature T cells.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

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

  1. 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]
  2. Bendelac A., Killeen N., Littman D. R., Schwartz R. H. A subset of CD4+ thymocytes selected by MHC class I molecules. Science. 1994 Mar 25;263(5154):1774–1778. doi: 10.1126/science.7907820. [DOI] [PubMed] [Google Scholar]
  3. Bix M., Coles M., Raulet D. Positive selection of V beta 8+ CD4-8- thymocytes by class I molecules expressed by hematopoietic cells. J Exp Med. 1993 Sep 1;178(3):901–908. doi: 10.1084/jem.178.3.901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. Carbone A. M., Marrack P., Kappler J. W. Demethylated CD8 gene in CD4+ T cells suggests that CD4+ cells develop from CD8+ precursors. Science. 1988 Nov 25;242(4882):1174–1176. doi: 10.1126/science.2460926. [DOI] [PubMed] [Google Scholar]
  6. Chan I. T., Limmer A., Louie M. C., Bullock E. D., Fung-Leung W. P., Mak T. W., Loh D. Y. Thymic selection of cytotoxic T cells independent of CD8 alpha-Lck association. Science. 1993 Sep 17;261(5128):1581–1584. doi: 10.1126/science.8372352. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Clayton L. K., Sieh M., Pious D. A., Reinherz E. L. Identification of human CD4 residues affecting class II MHC versus HIV-1 gp120 binding. Nature. 1989 Jun 15;339(6225):548–551. doi: 10.1038/339548a0. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. 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]
  11. Davignon J. L., Budd R. C., Ceredig R., Piguet P. F., MacDonald H. R., Cerottini J. C., Vassalli P., Izui S. Functional analysis of T cell subsets from mice bearing the lpr gene. J Immunol. 1985 Oct;135(4):2423–2428. [PubMed] [Google Scholar]
  12. 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]
  13. Fowlkes B. J., Edison L., Mathieson B. J., Chused T. M. Early T lymphocytes. Differentiation in vivo of adult intrathymic precursor cells. J Exp Med. 1985 Sep 1;162(3):802–822. doi: 10.1084/jem.162.3.802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. 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]
  16. Gay D., Maddon P., Sekaly R., Talle M. A., Godfrey M., Long E., Goldstein G., Chess L., Axel R., Kappler J. Functional interaction between human T-cell protein CD4 and the major histocompatibility complex HLA-DR antigen. Nature. 1987 Aug 13;328(6131):626–629. doi: 10.1038/328626a0. [DOI] [PubMed] [Google Scholar]
  17. Grusby M. J., Johnson R. S., Papaioannou V. E., Glimcher L. H. Depletion of CD4+ T cells in major histocompatibility complex class II-deficient mice. Science. 1991 Sep 20;253(5026):1417–1420. doi: 10.1126/science.1910207. [DOI] [PubMed] [Google Scholar]
  18. Haskins K., Kubo R., White J., Pigeon M., Kappler J., Marrack P. The major histocompatibility complex-restricted antigen receptor on T cells. I. Isolation with a monoclonal antibody. J Exp Med. 1983 Apr 1;157(4):1149–1169. doi: 10.1084/jem.157.4.1149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Herron L. R., Eisenberg R. A., Roper E., Kakkanaiah V. N., Cohen P. L., Kotzin B. L. Selection of the T cell receptor repertoire in Lpr mice. J Immunol. 1993 Oct 1;151(7):3450–3459. [PubMed] [Google Scholar]
  20. 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]
  21. Howe R. C., Pedrazzini T., MacDonald H. R. Functional responsiveness in vitro and in vivo of alpha/beta T cell receptors expressed by the B2A2 (J11d)- subset of CD4-8- thymocytes. Eur J Immunol. 1989 Jan;19(1):25–30. doi: 10.1002/eji.1830190105. [DOI] [PubMed] [Google Scholar]
  22. Ingold A. L., Landel C., Knall C., Evans G. A., Potter T. A. Co-engagement of CD8 with the T cell receptor is required for negative selection. Nature. 1991 Aug 22;352(6337):721–723. doi: 10.1038/352721a0. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Janeway C. A., Jr T-cell development. Accessories or coreceptors? Nature. 1988 Sep 15;335(6187):208–210. doi: 10.1038/335208a0. [DOI] [PubMed] [Google Scholar]
  25. Janeway C. A., Jr Thymic selection: two pathways to life and two to death. Immunity. 1994 Apr;1(1):3–6. doi: 10.1016/1074-7613(94)90003-5. [DOI] [PubMed] [Google Scholar]
  26. Killeen N., Sawada S., Littman D. R. Regulated expression of human CD4 rescues helper T cell development in mice lacking expression of endogenous CD4. EMBO J. 1993 Apr;12(4):1547–1553. doi: 10.1002/j.1460-2075.1993.tb05798.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Killeen N., Stuart S. G., Littman D. R. Development and function of T cells in mice with a disrupted CD2 gene. EMBO J. 1992 Dec;11(12):4329–4336. doi: 10.1002/j.1460-2075.1992.tb05532.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. 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]
  29. König R., Huang L. Y., Germain R. N. MHC class II interaction with CD4 mediated by a region analogous to the MHC class I binding site for CD8. Nature. 1992 Apr 30;356(6372):796–798. doi: 10.1038/356796a0. [DOI] [PubMed] [Google Scholar]
  30. Landolfi M. M., Van Houten N., Russell J. Q., Scollay R., Parnes J. R., Budd R. C. CD2-CD4-CD8- lymph node T lymphocytes in MRL lpr/lpr mice are derived from a CD2+CD4+CD8+ thymic precursor. J Immunol. 1993 Jul 15;151(2):1086–1096. [PubMed] [Google Scholar]
  31. Lo D., Ron Y., Sprent J. Induction of MHC-restricted specificity and tolerance in the thymus. Immunol Res. 1986;5(3):221–232. doi: 10.1007/BF02919203. [DOI] [PubMed] [Google Scholar]
  32. Maldonado M. A., Eisenberg R. A., Roper E., Cohen P. L., Kotzin B. L. Greatly reduced lymphoproliferation in lpr mice lacking major histocompatibility complex class I. J Exp Med. 1995 Feb 1;181(2):641–648. doi: 10.1084/jem.181.2.641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Malissen M., Gillet A., Ardouin L., Bouvier G., Trucy J., Ferrier P., Vivier E., Malissen B. Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene. EMBO J. 1995 Oct 2;14(19):4641–4653. doi: 10.1002/j.1460-2075.1995.tb00146.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Marrack P., Endres R., Shimonkevitz R., Zlotnik A., Dialynas D., Fitch F., Kappler J. The major histocompatibility complex-restricted antigen receptor on T cells. II. Role of the L3T4 product. J Exp Med. 1983 Oct 1;158(4):1077–1091. doi: 10.1084/jem.158.4.1077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Mixter P. F., Russell J. Q., Durie F. H., Budd R. C. Decreased CD4-CD8- TCR-alpha beta + cells in lpr/lpr mice lacking beta 2-microglobulin. J Immunol. 1995 Mar 1;154(5):2063–2074. [PubMed] [Google Scholar]
  36. Murphy K. M., Heimberger A. B., Loh D. Y. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science. 1990 Dec 21;250(4988):1720–1723. doi: 10.1126/science.2125367. [DOI] [PubMed] [Google Scholar]
  37. Ohteki T., Iwamoto M., Izui S., MacDonald H. R. Reduced development of CD4-8-B220+ T cells but normal autoantibody production in lpr/lpr mice lacking major histocompatibility complex class I molecules. Eur J Immunol. 1995 Jan;25(1):37–41. doi: 10.1002/eji.1830250108. [DOI] [PubMed] [Google Scholar]
  38. Potter T. A., Rajan T. V., Dick R. F., 2nd, Bluestone J. A. Substitution at residue 227 of H-2 class I molecules abrogates recognition by CD8-dependent, but not CD8-independent, cytotoxic T lymphocytes. Nature. 1989 Jan 5;337(6202):73–75. doi: 10.1038/337073a0. [DOI] [PubMed] [Google Scholar]
  39. 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]
  40. Robey E., Fowlkes B. J. Selective events in T cell development. Annu Rev Immunol. 1994;12:675–705. doi: 10.1146/annurev.iy.12.040194.003331. [DOI] [PubMed] [Google Scholar]
  41. Saint-Ruf C., Ungewiss K., Groettrup M., Bruno L., Fehling H. J., von Boehmer H. Analysis and expression of a cloned pre-T cell receptor gene. Science. 1994 Nov 18;266(5188):1208–1212. doi: 10.1126/science.7973703. [DOI] [PubMed] [Google Scholar]
  42. Salter R. D., Norment A. M., Chen B. P., Clayberger C., Krensky A. M., Littman D. R., Parham P. Polymorphism in the alpha 3 domain of HLA-A molecules affects binding to CD8. Nature. 1989 Mar 23;338(6213):345–347. doi: 10.1038/338345a0. [DOI] [PubMed] [Google Scholar]
  43. Sawada S., Scarborough J. D., Killeen N., Littman D. R. A lineage-specific transcriptional silencer regulates CD4 gene expression during T lymphocyte development. Cell. 1994 Jun 17;77(6):917–929. doi: 10.1016/0092-8674(94)90140-6. [DOI] [PubMed] [Google Scholar]
  44. Scollay R., Shortman K. Identification of early stages of T lymphocyte development in the thymus cortex and medulla. J Immunol. 1985 Jun;134(6):3632–3642. [PubMed] [Google Scholar]
  45. 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]
  46. 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]
  47. 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]
  48. Swain S. L. T cell subsets and the recognition of MHC class. Immunol Rev. 1983;74:129–142. doi: 10.1111/j.1600-065x.1983.tb01087.x. [DOI] [PubMed] [Google Scholar]
  49. Tiefenthaler G., Hanke T., Hünig T. Maturation of CD4-8- alpha/beta TCR+ T cells induced by CD2-stimulation in vivo and in vitro. Int Immunol. 1992 Jul;4(7):825–829. doi: 10.1093/intimm/4.7.825. [DOI] [PubMed] [Google Scholar]
  50. 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]
  51. Yagita H., Asakawa J., Tansyo S., Nakamura T., Habu S., Okumura K. Expression and function of CD2 during murine thymocyte ontogeny. Eur J Immunol. 1989 Dec;19(12):2211–2217. doi: 10.1002/eji.1830191206. [DOI] [PubMed] [Google Scholar]
  52. Yagüe J., White J., Coleclough C., Kappler J., Palmer E., Marrack P. The T cell receptor: the alpha and beta chains define idiotype, and antigen and MHC specificity. Cell. 1985 Aug;42(1):81–87. doi: 10.1016/s0092-8674(85)80103-3. [DOI] [PubMed] [Google Scholar]
  53. Zamoyska R., Vollmer A. C., Sizer K. C., Liaw C. W., Parnes J. R. Two Lyt-2 polypeptides arise from a single gene by alternative splicing patterns of mRNA. Cell. 1985 Nov;43(1):153–163. doi: 10.1016/0092-8674(85)90020-0. [DOI] [PubMed] [Google Scholar]
  54. Zúiga-Pflücker J. C., Jones L. A., Chin L. T., Kruisbeek A. M. CD4 and CD8 act as co-receptors during thymic selection of the T cell repertoire. Semin Immunol. 1991 May;3(3):167–175. [PubMed] [Google Scholar]
  55. von Boehmer H., Kirberg J., Rocha B. An unusual lineage of alpha/beta T cells that contains autoreactive cells. J Exp Med. 1991 Nov 1;174(5):1001–1008. doi: 10.1084/jem.174.5.1001. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES