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. 1988 Jul 1;168(1):143–156. doi: 10.1084/jem.168.1.143

Split tolerance induced by the intrathymic adoptive transfer of thymocyte stem cells

PMCID: PMC2188980  PMID: 2899619

Abstract

The intrathymic transfer of semiallogeneic CD4/CD8 double-negative (DN) thymocyte stem cells into irradiated host mice resulted in a transient state of chimerism in adoptive host thymus, spleen, and lymph nodes. Host-derived T cells, isolated from the thymus and periphery of the chimeric mice, were found to be specifically nonresponsive to the MHC antigens of the semiallogeneic DN donor in cytotoxicity assays. This nonresponsiveness was not permanent, but persisted as long as appreciable numbers of Thy-1 alloantigen-positive progeny of the DN donor cells could be detected in the spleen and lymph nodes of adoptive host mice. FACS sorting of DN donor cells before intrathymic transfer indicated that nonresponsiveness could be induced by Thy-1+ cells and was therefore not attributable to contaminating thymic macrophages, dendritic cells, or B cells. When FACS-sorted Thy-1+ (bm5 x bm12)F1 DN cells were transferred intrathymically into C57BL/6 hosts, nonresponsiveness to DN donor MHC class I but not class II alloantigen (split tolerance) was observed. These experiments were repeated using FACS-sorted Thy-1+ DN donor cells that were semiallogeneic to the irradiated adoptive host at either MHC class I or class II locus with similar results. Limiting dilution analysis showed that host-derived CTL precursors were tolerant of DN donor MHC class I alloantigen and no evidence for the involvement of suppressor T cells was found. The data indicate that murine thymocytes themselves are capable of tolerizing to MHC class I but not class II alloantigen after intrathymic transfer. The implications for intrathymic T cell differentiation and maintenance of self tolerance are discussed.

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Selected References

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  1. 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]
  2. Babbitt B. P., Allen P. M., Matsueda G., Haber E., Unanue E. R. Binding of immunogenic peptides to Ia histocompatibility molecules. 1985 Sep 26-Oct 2Nature. 317(6035):359–361. doi: 10.1038/317359a0. [DOI] [PubMed] [Google Scholar]
  3. Bevan M. J. In a radiation chimaera, host H-2 antigens determine immune responsiveness of donor cytotoxic cells. Nature. 1977 Sep 29;269(5627):417–418. doi: 10.1038/269417a0. [DOI] [PubMed] [Google Scholar]
  4. Dennert G., Hyman R., Lesley J., Trowbridge I. S. Effects of cytotoxic monoclonal antibody specific for T200 glycoprotein on functional lymphoid cell populations. Cell Immunol. 1980 Aug 1;53(2):350–364. doi: 10.1016/0008-8749(80)90335-4. [DOI] [PubMed] [Google Scholar]
  5. Dialynas D. P., Quan Z. S., Wall K. A., Pierres A., Quintáns J., Loken M. R., Pierres M., Fitch F. W. Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: similarity of L3T4 to the human Leu-3/T4 molecule. J Immunol. 1983 Nov;131(5):2445–2451. [PubMed] [Google Scholar]
  6. Farr A. G., Anderson S. K., Marrack P., Kappler J. Expression of antigen-specific, major histocompatibility complex-restricted receptors by cortical and medullary thymocytes in situ. Cell. 1985 Dec;43(2 Pt 1):543–550. doi: 10.1016/0092-8674(85)90183-7. [DOI] [PubMed] [Google Scholar]
  7. Fink P. J., Weissman I. L., Bevan M. J. Haplotype-specific suppression of cytotoxic T cell induction by antigen inappropriately presented on T cells. J Exp Med. 1983 Jan 1;157(1):141–154. doi: 10.1084/jem.157.1.141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. 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]
  9. Goldschneider I., Komschlies K. L., Greiner D. L. Studies of thymocytopoiesis in rats and mice. I. Kinetics of appearance of thymocytes using a direct intrathymic adoptive transfer assay for thymocyte precursors. J Exp Med. 1986 Jan 1;163(1):1–17. doi: 10.1084/jem.163.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Jenkins M. K., Schwartz R. H. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med. 1987 Feb 1;165(2):302–319. doi: 10.1084/jem.165.2.302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Jenkinson E. J., Jhittay P., Kingston R., Owen J. J. Studies of the role of the thymic environment in the induction of tolerance to MHC antigens. Transplantation. 1985 Mar;39(3):331–333. doi: 10.1097/00007890-198503000-00030. [DOI] [PubMed] [Google Scholar]
  12. Jerne N. K. The somatic generation of immune recognition. Eur J Immunol. 1971 Jan;1(1):1–9. doi: 10.1002/eji.1830010102. [DOI] [PubMed] [Google Scholar]
  13. Jordan R. K., Robinson J. H., Hopkinson N. A., House K. C., Bentley A. L. Thymic epithelium and the induction of transplantation tolerance in nude mice. Nature. 1985 Apr 4;314(6010):454–456. doi: 10.1038/314454a0. [DOI] [PubMed] [Google Scholar]
  14. Kappler J. W., Roehm N., Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987 Apr 24;49(2):273–280. doi: 10.1016/0092-8674(87)90568-x. [DOI] [PubMed] [Google Scholar]
  15. Kisielow P., Leiserson W., Von Boehmer H. Differentiation of thymocytes in fetal organ culture: analysis of phenotypic changes accompanying the appearance of cytolytic and interleukin 2-producing cells. J Immunol. 1984 Sep;133(3):1117–1123. [PubMed] [Google Scholar]
  16. Lo D., Sprent J. Identity of cells that imprint H-2-restricted T-cell specificity in the thymus. Nature. 1986 Feb 20;319(6055):672–675. doi: 10.1038/319672a0. [DOI] [PubMed] [Google Scholar]
  17. Marshak-Rothstein A., Fink P., Gridley T., Raulet D. H., Bevan M. J., Gefter M. L. Properties and applications of monoclonal antibodies directed against determinants of the Thy-1 locus. J Immunol. 1979 Jun;122(6):2491–2497. [PubMed] [Google Scholar]
  18. Mathieson B. J., Sharrow S. O., Rosenberg Y., Hämmerling U. Lyt 1+23- cells appear in the thymus before Lyt 123+ cells. Nature. 1981 Jan 15;289(5794):179–181. doi: 10.1038/289179a0. [DOI] [PubMed] [Google Scholar]
  19. Muraoka S., Miller R. G. Cells in bone marrow and in T cell colonies grown from bone marrow can suppress generation of cytotoxic T lymphocytes directed against their self antigens. J Exp Med. 1980 Jul 1;152(1):54–71. doi: 10.1084/jem.152.1.54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ohki H., Martin C., Corbel C., Coltey M., Le Douarin N. M. Tolerance induced by thymic epithelial grafts in birds. Science. 1987 Aug 28;237(4818):1032–1035. doi: 10.1126/science.3616623. [DOI] [PubMed] [Google Scholar]
  21. Quill H., Schwartz R. H. Stimulation of normal inducer T cell clones with antigen presented by purified Ia molecules in planar lipid membranes: specific induction of a long-lived state of proliferative nonresponsiveness. J Immunol. 1987 Jun 1;138(11):3704–3712. [PubMed] [Google Scholar]
  22. Ready A. R., Jenkinson E. J., Kingston R., Owen J. J. Successful transplantation across major histocompatibility barrier of deoxyguanosine-treated embryonic thymus expressing class II antigens. Nature. 1984 Jul 19;310(5974):231–233. doi: 10.1038/310231a0. [DOI] [PubMed] [Google Scholar]
  23. Sarmiento M., Glasebrook A. L., Fitch F. W. IgG or IgM monoclonal antibodies reactive with different determinants on the molecular complex bearing Lyt 2 antigen block T cell-mediated cytolysis in the absence of complement. J Immunol. 1980 Dec;125(6):2665–2672. [PubMed] [Google Scholar]
  24. Shimonkevitz R. P., Husmann L. A., Bevan M. J., Crispe I. N. Transient expression of IL-2 receptor precedes the differentiation of immature thymocytes. Nature. 1987 Sep 10;329(6135):157–159. doi: 10.1038/329157a0. [DOI] [PubMed] [Google Scholar]
  25. Von Boehmer H., Schubiger K. Thymocytes appear to ignore class I major histocompatibility complex antigens expressed on thymus epithelial cells. Eur J Immunol. 1984 Nov;14(11):1048–1052. doi: 10.1002/eji.1830141116. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Zinkernagel R. M., Doherty P. C. MHC-restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness. Adv Immunol. 1979;27:51–177. doi: 10.1016/s0065-2776(08)60262-x. [DOI] [PubMed] [Google Scholar]
  28. Zinkernagel R. M. Selection of restriction specificities of virus-specific cytotoxic T cells in the thymus: no evidence for a crucial role of antigen-presenting cells. J Exp Med. 1982 Dec 1;156(6):1842–1847. doi: 10.1084/jem.156.6.1842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. von Boehmer H., Hafen K. Minor but not major histocompatibility antigens of thymus epithelium tolerize precursors of cytolytic T cells. Nature. 1986 Apr 17;320(6063):626–628. doi: 10.1038/320626a0. [DOI] [PubMed] [Google Scholar]

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