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J Exp Med. Dec 1, 1996; 184(6): 2393–2398.
PMCID: PMC2196374
Brief Definitive Reports
The Thymus Contains a High Frequency of Cells that Prevent Autoimmune Diabetes on Transfer into Prediabetic Recipients
Abdelhadi Saoudi, Benedict Seddon,* Debbie Fowell,§ and Don Mason*
From the *Medical Research Council Cellular Immunology Unit, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE United Kingdom; Institute National de la Santé et de la Recherche Médicale U28, Hôpital Purpan, 31059, Toulouse, France; and §Infectious Disease Division, University of California, San Francisco, California 94143-0654
Address correspondence to Ben Seddon, MRC Cellular Immunology Unit, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
Received July 8, 1996; Revised September 23, 1996
Abstract
Rats of the PVG.RT1u strain develop autoimmune diabetes when thymectomized at 6 wk of age and are rendered relatively lymphopenic by a cumulative dose of 1,000 rads 137Cs γ-irradiation given in four split doses. Previous studies have shown that the disease is prevented by the intravenous injection of 5 × 106 CD4+ CD45RC TCRαβ+ RT6+ peripheral T cells from normal syngeneic donors. These cells have a memory phenotype and are presumably primed to some extrathymic antigen. However, we now report that the CD4+ CD8 population of mature thymocytes is a very potent source of cells, with the capacity to prevent diabetes in our lymphopenic animals. As few as 6 × 105 of these cells protect ~50% of recipients and the level of protection increases with cell dose. It appears that one characteristic of the intrathymic selection of the T cell repertoire is the generation of cells that regulate the autoimmune potential of peripheral T cells that have been neither clonally deleted intrathymically nor rendered irreversibly anergic in the periphery.
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Selected References
These references are in PubMed. This may not be the complete list of references from this article.
1. Kappler JW, Roehm M, Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987;49:273–280. [PubMed]
2. Mueller DL, Jenkins MK, Schwartz RH. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445–480. [PubMed]
3. Nickoloff BJ, Turka LA. Immunological functions of non-professional antigen-presenting cells: new insights from studies of T-cell interactions with keratinocytes. Immunol Today. 1994;15:464–469. [PubMed]
4. Ohashi PS, Oehen S, Buerki K, Pircher H, Ohashi CT, Odermatt B, Malissen B, Zinkernagel RM, Hengartner H. Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice. Cell. 1991;65:305–317. [PubMed]
5. Coutinho A, Salaun J, Corbel C, Bandeira A, Le Douarin N. The role of thymic epithelium in the establishment of transplantation tolerance. Immunol Rev. 1993;133:225–240. [PubMed]
6. Zamoyska R, Waldmann H, Matzinger P. Peripheral tolerance mechanisms prevent the development of autoreactive T cells in chimeras grafted with two minor incompatible thymuses. Eur J Immunol. 1989;19:111–117. [PubMed]
7. Fukuma K, Sakaguchi S, Kuribayashi K, Chen WL, Morishita R, Sekita K, Uchino H, Masuda T. Immunologic and clinical studies on murine experimental autoimmune gastritis induced by neonatal thymectomy. Gastroenterology. 1988;94:274–283. [PubMed]
8. Stumbles PA, Penhale WJ. IDDM in rats induced by thymectomy and irradiation. Diabetes. 1993;42:571–578. [PubMed]
9. Fowell D, Mason DW. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+T cell subset that inhibits this autoimmune potential. J Exp Med. 1993;177:627–636. [PMC free article] [PubMed]
10. Cairns L, Rosen FS, Borel Y. Mice naturally tolerant to C5 have T cells that suppress the response to this antigen. Eur J Immunol. 1986;16:1277–1282. [PubMed]
11. Lafaille JJ, Nagashima K, Katsuki M, Tonegawa S. High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice. Cell. 1994;78:399–408. [PubMed]
12. Saoudi A, Seddon B, Heath V, Fowell V, Mason D. The physiological role of regulatory T cells in the prevention of autoimmunity: the function of the thymus in the generation of the regulatory T cell subset. Immunol Rev. 1996;149:195–216. [PubMed]
13. Williams AF, Galfré G, Milstein C. Analysis of cell surface by xenogeneic myeloma-hybrid antibodies: differentiation antigens of rat lymphocytes. Cell. 1977;12:663–673. [PubMed]
14. McCall MN, Shotton DM, Barclay AN. Expression of soluble isoforms of rat CD45. Analysis by electron microscopy and use in epitope mapping of anti-CD45R monoclonal antibodies. Immunology. 1992;76:310–317. [PubMed]
15. Spickett GP, Brandon MR, Mason DW, Williams AF, Woollett GR. MRC OX-22, a monoclonal antibody that labels a new subset of T lymphocytes and reacts with the high molecular weight form of the leukocyte-common antigen. J Exp Med. 1983;158:795–810. [PMC free article] [PubMed]
16. Woollett GR, Barclay AN, Puklavec M, Williams AF. Molecular and antigenic heterogeneity of the rat leukocyte-common antigen from thymocytes and T and B lymphocytes. Eur J Immunol. 1985;15:168–173. [PubMed]
17. Hunt SV, Fowler MH. A repopulation assay for B and T lymphocyte stem cells employing radiation chimaeras. Cell Tissue Kinetics. 1981;14:445–464. [PubMed]
18. McMaster WR, Williams AF. Identification of Ia glycoproteins in rat thymus and purification from rat spleen. Eur J Immunol. 1979;9:426–433. [PubMed]
19. Brideau RJ, Carter PB, McMaster WR, Webb M. Two subsets of rat T lymphocytes defined with monoclonal antibodies. Eur J Immunol. 1980;10:609–615. [PubMed]
20. Hsiung LM, Barclay AN, Brandon MR, Sim E, Porter RR. Purification of human C3b inactivator by monoclonal-antibody affinity chromatography. Biochem J. 1982;203:293–298. [PubMed]
21. Jensenius JC, Williams AF. The binding of anti-immunoglobulin antibodies to rat thymocytes and thoracic duct lymphocytes. Eur J Immunol. 1974;4:91–97. [PubMed]
22. Gowans JL, Knight EJ. The role of re-circulation of lymphocytes in the rat. Proc R Soc Lond B Biol Soc. 1964;159:257–282. [PubMed]
23. Mason, D.W., W.J. Penhale, and J.D. Sedgwick. 1987. Preparation of lymphocyte subpopulations. In Lymphocytes. 1 ed. G.G.B. Klaus, editor. IRL Press, Oxford. 35–54.
24. Bunce JV, Mason DW. The tolerization of rat thymocytes to xenogeneic erythrocytes: kinetics of induction and recovery. Eur J Immunol. 1981;11:889–896. [PubMed]
25. Seddon, B., A. Saoudi, M. Nicholson, and D. Mason. 1996. CD4+CD8- thymocytes that express L-Selectin protect rats from diabetes upon adoptive transfer. Eur. J. Immunol. In press.
26. Padovan E, Casorati G, Dellabona P, Meyer S, Brockhaus M, Lanzavecchia A. Expression of two T cell receptor alpha chains: dual receptor T cells. Science (Wash DC) 1993;262:422–424. [PubMed]
27. Heath WR, Miller JF. Expression of two alpha chains on the surface of T cells in T cell receptor transgenic mice. J Exp Med. 1993;178:1807–1811. [PMC free article] [PubMed]
28. Mason D. Allelic exclusion of α chains in TCRs. Int Immunol. 1994;6:881–885. [PubMed]
29. Le Douarin N, Corbel C, Bandeira A, Thomas-Vaslin V, Modigliani Y, Coutinho A, Salaün J. Evidence for a thymus-dependent form of tolerance that is not based on elimination or anergy of reactive T cells. Immunol Rev. 1996;149:35–54. [PubMed]
30. Jolicoeur C, Hanahan D, Smith KM. T–cell tolerance toward a transgenic beta-cell antigen and transcription of endogenous pancreatic genes in thymus. Proc Natl Acad Sci USA. 1994;91:6707–6711. [PubMed]
31. Fowell, D., F. Powrie, A. Saoudi, B. Seddon, V. Heath, and D. Mason. 1995. The role of subsets of CD4+ T cells in autoimmunity. In T Cell Subsets in Infectious and Autoimmune Diseases. D. Chadwick and C. Cardew, editors. John Wiley & Sons, Ltd., Chichester, UK. 173–182.
32. Antonia SJ, Geiger T, Miller J, Flavell RA. Mechanisms of immune tolerance induction through the thymic expression of a peripheral tissue-specific protein. Int Immunol. 1995;7:715–725. [PubMed]
33. Heath WR, Allison J, Hoffmann MW, Schonrich G, Hammerling G, Arnold B, Miller JFAP. Autoimmune diabetes as a consequence of locally produced interleukin-2. Nature (Lond) 1992;359:547–549. [PubMed]
34. Muir A, Peck A, Clare-Salzler M, Song YH, Cornelius J, Luchetta R, Krischer J, Maclaren N. Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferongamma transcription. J Clin Invest. 1995;95:628–634. [PMC free article] [PubMed]
35. Parish NM, Hutchings PR, O'Reilly L, QuarteyPapafio R, Healey D, Ozegbe P, Cooke A. Tolerance induction as a therapeutic strategy for the control of autoimmune endocrine disease in mouse models. Immunol Rev. 1995;144:269–300. [PubMed]
36. Morahan G, Allison J, Miller JFAP. Tolerance of class I histocompatibility antigens expressed extrathymically. Nature (Lond) 1989;339:622–624. [PubMed]
37. Powrie F, Mason D. OX-22high CD4+ T cells induce wasting disease with multiple organ pathology: prevention by the OX-22lowsubset. J Exp Med. 1990;172:1701–1708. [PMC free article] [PubMed]
38. Eishi Y, McCullagh P. Acquisition of immunological self-recognition by the fetal rat. Immunology. 1988;64:319–323. [PubMed]
39. Ohki H, Martin C, Corbel C, Coltey M, Le Douarin N. Tolerance induced by thymic epithelium grafts in birds. Science (Wash DC) 1987;237:1032–1035. [PubMed]
40. Kojima A, Tanaka-Kojima Y, Sakakura T, Nishizuka Y. Spontaneous development of autoimmune thyroiditis in neonatally thymectomized mice. Lab Invest. 1976;34:550–557. [PubMed]
41. Taguchi O, Nishizuka Y, Sakakura T, Kojima A. Autoimmune oophoritis in thymectomized mice: detection of circulating antibodies against oocytes. Clin Exp Immunol. 1980;40:540–553. [PubMed]
42. Sakaguchi S, Takahashi T, Nishizuka Y. Study on cellular events in post-thymectomy autoimmune oophoritis in mice. II. Requirement of Lyt-1 cells in normal female mice for the prevention of oophoritis. J Exp Med. 1982;156:1577–1586. [PMC free article] [PubMed]
Figures and Tables
Figure 1
Figure 1
CD4+CD8 thymocytes are more potent than peripheral CD4+CD45RC T cells in protecting from diabetes. T cells subsets were negatively selected from TDLs or thymus from normal PVG.RT1u rats by rosette depletion as described (more ...)
Figure 2
Figure 2
Naive CD4+CD8 thymocytes are less potent in providing in vivo B cell help than primed peripheral CD4+ T cells. Primed CD4+ T cells and primed B cells were negatively selected from TDLs from PVG.RT1c rats primed with (more ...)
Table 1
Table 1
Comparison of Experimental and Theoretical Results on Control of Diabetes by CD4+CD8 Thymocytes
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