Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1992 Mar 1;175(3):731–742. doi: 10.1084/jem.175.3.731

Activation events during thymic selection

PMCID: PMC2119155  PMID: 1740662

Abstract

During their differentiation in the mouse thymus, CD4+8- cells undergo several of the sequential changes observed upon normal activation of mature, peripheral CD4+ lymphocytes. Expression of CD69, an early activation marker, is first observed on a minority of cells at the T cell receptor (TCR)lo/med double-positive stage, is maximal (50-90%) on heat-stable antigen (HSA)hi TCRhi double-positive, HSAhi TCRmed CD4+8lo, and HSAhi TCRhi CD4+8- cells, and is downmodulated at the mature HSAlo CD4+8- stage. In contrast, CD44, a late activation marker, is selectively expressed at the HSAlo stage. The set of lymphokines that CD4+8- thymocytes can produce upon stimulation also characteristically expands from mainly interleukin 2 (IL-2) at the HSAhi stage, to IL-2 and very large amounts of IL-4, IL-5, IL-10, and interferon gamma (IFN-gamma) at the HSAlo stage. 1 in 30 HSAlo CD4+8- adult thymocytes secrete IL-4 upon stimulation through their TCR. This frequency is 25% of the frequency of IL-2 producers, about 100-fold above that of peripheral (mainly resting) CD4+ T cells. With time after their generation in organ culture, CD4+8- thymocytes lose their capacity to secrete IL-4, IL-5, and IFN-gamma, but not IL-2. Similarly, the frequency of IL-4, but not of IL-2, producers progressively decreases after emigration to the periphery as judged by direct comparison between thymic and splenic CD4+ cells in newborns, or by following the fate of intrathymically labeled CD4+8- cells in adults after their migration to the spleen. This sequence suggests that thymic selection results from an activation process rather than a simple rescue from death at the double-positive stage, and shows that the functional changes induced after intrathymic activation, although transient, are still evident after export to the periphery.

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. Adkins B. Developmental regulation of the intrathymic T cell precursor population. J Immunol. 1991 Mar 1;146(5):1387–1393. [PubMed] [Google Scholar]
  2. Agus D. B., Surh C. D., Sprent J. Reentry of T cells to the adult thymus is restricted to activated T cells. J Exp Med. 1991 May 1;173(5):1039–1046. doi: 10.1084/jem.173.5.1039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Andersson U., Andersson J., Lindfors A., Wagner K., Möller G., Heusser C. H. Simultaneous production of interleukin 2, interleukin 4 and interferon-gamma by activated human blood lymphocytes. Eur J Immunol. 1990 Jul;20(7):1591–1596. doi: 10.1002/eji.1830200727. [DOI] [PubMed] [Google Scholar]
  4. Ben-Sasson S. Z., Le Gros G., Conrad D. H., Finkelman F. D., Paul W. E. IL-4 production by T cells from naive donors. IL-2 is required for IL-4 production. J Immunol. 1990 Aug 15;145(4):1127–1136. [PubMed] [Google Scholar]
  5. Bendelac A., Schwartz R. H. Th0 cells in the thymus: the question of T-helper lineages. Immunol Rev. 1991 Oct;123:169–188. doi: 10.1111/j.1600-065x.1991.tb00610.x. [DOI] [PubMed] [Google Scholar]
  6. Bradley L. M., Duncan D. D., Tonkonogy S., Swain S. L. Characterization of antigen-specific CD4+ effector T cells in vivo: immunization results in a transient population of MEL-14-, CD45RB- helper cells that secretes interleukin 2 (IL-2), IL-3, IL-4, and interferon gamma. J Exp Med. 1991 Sep 1;174(3):547–559. doi: 10.1084/jem.174.3.547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Budd R. C., Cerottini J. C., Horvath C., Bron C., Pedrazzini T., Howe R. C., MacDonald H. R. Distinction of virgin and memory T lymphocytes. Stable acquisition of the Pgp-1 glycoprotein concomitant with antigenic stimulation. J Immunol. 1987 May 15;138(10):3120–3129. [PubMed] [Google Scholar]
  8. Budd R. C., Cerottini J. C., MacDonald H. R. Selectively increased production of interferon-gamma by subsets of Lyt-2+ and L3T4+ T cells identified by expression of Pgp-1. J Immunol. 1987 Jun 1;138(11):3583–3586. [PubMed] [Google Scholar]
  9. Ceredig R. Intrathymic proliferation of perinatal mouse alpha beta and gamma delta T cell receptor-expressing mature T cells. Int Immunol. 1990;2(9):859–867. doi: 10.1093/intimm/2.9.859. [DOI] [PubMed] [Google Scholar]
  10. Cherwinski H. M., Schumacher J. H., Brown K. D., Mosmann T. R. Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J Exp Med. 1987 Nov 1;166(5):1229–1244. doi: 10.1084/jem.166.5.1229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Egerton M., Scollay R. Intrathymic selection of murine TCR alpha beta+CD4-CD8- thymocytes. Int Immunol. 1990;2(2):157–163. doi: 10.1093/intimm/2.2.157. [DOI] [PubMed] [Google Scholar]
  12. Ehlers S., Smith K. A. Differentiation of T cell lymphokine gene expression: the in vitro acquisition of T cell memory. J Exp Med. 1991 Jan 1;173(1):25–36. doi: 10.1084/jem.173.1.25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fink P. J., Bevan M. J., Weissman I. L. Thymic cytotoxic T lymphocytes are primed in vivo to minor histocompatibility antigens. J Exp Med. 1984 Feb 1;159(2):436–451. doi: 10.1084/jem.159.2.436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Finkel T. H., Cambier J. C., Kubo R. T., Born W. K., Marrack P., Kappler J. W. The thymus has two functionally distinct populations of immature alpha beta + T cells: one population is deleted by ligation of alpha beta TCR. Cell. 1989 Sep 22;58(6):1047–1054. doi: 10.1016/0092-8674(89)90503-5. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Gossmann J., Löhler J., Lehmann-Grube F. Entry of antivirally active T lymphocytes into the thymus of virus-infected mice. J Immunol. 1991 Jan 1;146(1):293–297. [PubMed] [Google Scholar]
  17. Groves E. S., Singer A. Role of the H-2 complex in the induction of T cell tolerance to self minor histocompatibility antigens. J Exp Med. 1983 Nov 1;158(5):1483–1497. doi: 10.1084/jem.158.5.1483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Guidos C. J., Danska J. S., Fathman C. G., Weissman I. L. T cell receptor-mediated negative selection of autoreactive T lymphocyte precursors occurs after commitment to the CD4 or CD8 lineages. J Exp Med. 1990 Sep 1;172(3):835–845. doi: 10.1084/jem.172.3.835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hirokawa K., Utsuyama M., Sado T. Immunohistological analysis of immigration of thymocyte-precursors into the thymus: evidence for immigration of peripheral T cells into the thymic medulla. Cell Immunol. 1989 Mar;119(1):160–170. doi: 10.1016/0008-8749(89)90232-3. [DOI] [PubMed] [Google Scholar]
  20. Hu-Li J., Ohara J., Watson C., Tsang W., Paul W. E. Derivation of a T cell line that is highly responsive to IL-4 and IL-2 (CT.4R) and of an IL-2 hyporesponsive mutant of that line (CT.4S). J Immunol. 1989 Feb 1;142(3):800–807. [PubMed] [Google Scholar]
  21. Ikuta K., Kina T., MacNeil I., Uchida N., Peault B., Chien Y. H., Weissman I. L. A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells. Cell. 1990 Sep 7;62(5):863–874. doi: 10.1016/0092-8674(90)90262-d. [DOI] [PubMed] [Google Scholar]
  22. Jotereau F., Heuze F., Salomon-Vie V., Gascan H. Cell kinetics in the fetal mouse thymus: precursor cell input, proliferation, and emigration. J Immunol. 1987 Feb 15;138(4):1026–1030. [PubMed] [Google Scholar]
  23. Karlsson L., Surh C. D., Sprent J., Peterson P. A. A novel class II MHC molecule with unusual tissue distribution. Nature. 1991 Jun 6;351(6326):485–488. doi: 10.1038/351485a0. [DOI] [PubMed] [Google Scholar]
  24. Kelly K. A., Scollay R. Analysis of recent thymic emigrants with subset- and maturity-related markers. Int Immunol. 1990;2(5):419–425. doi: 10.1093/intimm/2.5.419. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Le Gros G., Ben-Sasson S. Z., Seder R., Finkelman F. D., Paul W. E. Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J Exp Med. 1990 Sep 1;172(3):921–929. doi: 10.1084/jem.172.3.921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lynch F., Ceredig R. Mouse strain variation in Ly-24 (Pgp-1) expression by peripheral T cells and thymocytes: implications for T cell differentiation. Eur J Immunol. 1989 Feb;19(2):223–229. doi: 10.1002/eji.1830190202. [DOI] [PubMed] [Google Scholar]
  28. Michie S. A., Kirkpatrick E. A., Rouse R. V. Rare peripheral T cells migrate to and persist in normal mouse thymus. J Exp Med. 1988 Nov 1;168(5):1929–1934. doi: 10.1084/jem.168.5.1929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
  30. Murphy D. B., Lo D., Rath S., Brinster R. L., Flavell R. A., Slanetz A., Janeway C. A., Jr A novel MHC class II epitope expressed in thymic medulla but not cortex. Nature. 1989 Apr 27;338(6218):765–768. doi: 10.1038/338765a0. [DOI] [PubMed] [Google Scholar]
  31. Nussenzweig M. C., Steinman R. M. Contribution of dendritic cells to stimulation of the murine syngeneic mixed leukocyte reaction. J Exp Med. 1980 May 1;151(5):1196–1212. doi: 10.1084/jem.151.5.1196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ohara J., Paul W. E. Production of a monoclonal antibody to and molecular characterization of B-cell stimulatory factor-1. Nature. 1985 May 23;315(6017):333–336. doi: 10.1038/315333a0. [DOI] [PubMed] [Google Scholar]
  33. Ortega G., Robb R. J., Shevach E. M., Malek T. R. The murine IL 2 receptor. I. Monoclonal antibodies that define distinct functional epitopes on activated T cells and react with activated B cells. J Immunol. 1984 Oct;133(4):1970–1975. [PubMed] [Google Scholar]
  34. Penit C. In vivo thymocyte maturation. BUdR labeling of cycling thymocytes and phenotypic analysis of their progeny support the single lineage model. J Immunol. 1986 Oct 1;137(7):2115–2121. [PubMed] [Google Scholar]
  35. Penit C., Vasseur F. Cell proliferation and differentiation in the fetal and early postnatal mouse thymus. J Immunol. 1989 May 15;142(10):3369–3377. [PubMed] [Google Scholar]
  36. Rocha B., Bandeira A. Limiting dilution analysis of interleukin-2-producing mature T cells. Interleukin 2 secretion is an exclusive property of L3T4+ lymphocytes. Scand J Immunol. 1988 Jan;27(1):47–57. doi: 10.1111/j.1365-3083.1988.tb02322.x. [DOI] [PubMed] [Google Scholar]
  37. Rudensky AYu, Rath S., Preston-Hurlburt P., Murphy D. B., Janeway C. A., Jr On the complexity of self. Nature. 1991 Oct 17;353(6345):660–662. doi: 10.1038/353660a0. [DOI] [PubMed] [Google Scholar]
  38. Schneider R., Lees R. K., Pedrazzini T., Zinkernagel R. M., Hengartner H., MacDonald H. R. Postnatal disappearance of self-reactive (V beta 6+) cells from the thymus of Mlsa mice. Implications for T cell development and autoimmunity. J Exp Med. 1989 Jun 1;169(6):2149–2158. doi: 10.1084/jem.169.6.2149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Schumacher J. H., O'Garra A., Shrader B., van Kimmenade A., Bond M. W., Mosmann T. R., Coffman R. L. The characterization of four monoclonal antibodies specific for mouse IL-5 and development of mouse and human IL-5 enzyme-linked immunosorbent. J Immunol. 1988 Sep 1;141(5):1576–1581. [PubMed] [Google Scholar]
  40. 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]
  41. Seder R. A., Le Gros G., Ben-Sasson S. Z., Urban J., Jr, Finkelman F. D., Paul W. E. Increased frequency of interleukin 4-producing T cells as a result of polyclonal priming. Use of a single-cell assay to detect interleukin 4-producing cells. Eur J Immunol. 1991 May;21(5):1241–1247. doi: 10.1002/eji.1830210522. [DOI] [PubMed] [Google Scholar]
  42. Shortman K., Vremec D., Egerton M. The kinetics of T cell antigen receptor expression by subgroups of CD4+8+ thymocytes: delineation of CD4+8+3(2+) thymocytes as post-selection intermediates leading to mature T cells. J Exp Med. 1991 Feb 1;173(2):323–332. doi: 10.1084/jem.173.2.323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Springer T., Galfrè G., Secher D. S., Milstein C. Monoclonal xenogeneic antibodies to murine cell surface antigens: identification of novel leukocyte differentiation antigens. Eur J Immunol. 1978 Aug;8(8):539–551. doi: 10.1002/eji.1830080802. [DOI] [PubMed] [Google Scholar]
  44. Stutman O. Intrathymic and extrathymic T cell maturation. Immunol Rev. 1978;42:138–184. doi: 10.1111/j.1600-065x.1978.tb00261.x. [DOI] [PubMed] [Google Scholar]
  45. Swain S. L., McKenzie D. T., Weinberg A. D., Hancock W. Characterization of T helper 1 and 2 cell subsets in normal mice. Helper T cells responsible for IL-4 and IL-5 production are present as precursors that require priming before they develop into lymphokine-secreting cells. J Immunol. 1988 Nov 15;141(10):3445–3455. [PubMed] [Google Scholar]
  46. Swain S. L., Weinberg A. D., English M. CD4+ T cell subsets. Lymphokine secretion of memory cells and of effector cells that develop from precursors in vitro. J Immunol. 1990 Mar 1;144(5):1788–1799. [PubMed] [Google Scholar]
  47. Swain S. L., Weinberg A. D., English M., Huston G. IL-4 directs the development of Th2-like helper effectors. J Immunol. 1990 Dec 1;145(11):3796–3806. [PubMed] [Google Scholar]
  48. Takahama Y., Sharrow S. O., Singer A. Expression of an unusual T cell receptor (TCR)-V beta repertoire by Ly-6C+ subpopulations of CD4+ and/or CD8+ thymocytes. Evidence for a developmental relationship between Ly-6C+ thymocytes and CD4-CD8-TCR-alpha beta+ thymocytes. J Immunol. 1991 Nov 1;147(9):2883–2891. [PubMed] [Google Scholar]
  49. Taswell C. Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis. J Immunol. 1981 Apr;126(4):1614–1619. [PubMed] [Google Scholar]
  50. Testi R., Phillips J. H., Lanier L. L. Constitutive expression of a phosphorylated activation antigen (Leu 23) by CD3bright human thymocytes. J Immunol. 1988 Oct 15;141(8):2557–2563. [PubMed] [Google Scholar]
  51. Testi R., Phillips J. H., Lanier L. L. Leu 23 induction as an early marker of functional CD3/T cell antigen receptor triggering. Requirement for receptor cross-linking, prolonged elevation of intracellular [Ca++] and stimulation of protein kinase C. J Immunol. 1989 Mar 15;142(6):1854–1860. [PubMed] [Google Scholar]
  52. Trowbridge I. S., Lesley J., Schulte R., Hyman R., Trotter J. Biochemical characterization and cellular distribution of a polymorphic, murine cell-surface glycoprotein expressed on lymphoid tissues. Immunogenetics. 1982 Mar;15(3):299–312. doi: 10.1007/BF00364338. [DOI] [PubMed] [Google Scholar]
  53. Webb S. R., Sprent J. Induction of neonatal tolerance to Mlsa antigens by CD8+ T cells. Science. 1990 Jun 29;248(4963):1643–1646. doi: 10.1126/science.1973003. [DOI] [PubMed] [Google Scholar]
  54. 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]

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

RESOURCES