Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Jan 1;183(1):67–76. doi: 10.1084/jem.183.1.67

CD8 T cell clones from young nonobese diabetic (NOD) islets can transfer rapid onset of diabetes in NOD mice in the absence of CD4 cells

PMCID: PMC2192404  PMID: 8551245

Abstract

T cells play an important role in the pathogenesis of diabetes in the nonobese diabetic (NOD) mouse. CD8 cytotoxic T cell lines and clones were generated from the lymphocytic infiltrate in the islets of Langerhans of young (7-wk-old). NOD mice by growing them on (NOD x B6- RIP-B7-1)F1 islets. These cells proliferate specifically to NOD islets and kill NOD islets in vitro. The cells are restricted by H-2Kd, and all bear T cell antigen receptor encoded by V beta 6. When these CD8 T cell lines and clones are adoptively transferred to irradiated female NOD, young NOD-SCID, and CB17-SCID mice, diabetes occurs very rapidly, within 10 d of transfer and without CD4 T cells.

Full Text

The Full Text of this article is available as a PDF (1.9 MB).

Selected References

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

  1. Bendelac A., Carnaud C., Boitard C., Bach J. F. Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt-2+ T cells. J Exp Med. 1987 Oct 1;166(4):823–832. doi: 10.1084/jem.166.4.823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bottazzo G. F., Dean B. M., McNally J. M., MacKay E. H., Swift P. G., Gamble D. R. In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis. N Engl J Med. 1985 Aug 8;313(6):353–360. doi: 10.1056/NEJM198508083130604. [DOI] [PubMed] [Google Scholar]
  3. Chen L., Ashe S., Brady W. A., Hellström I., Hellström K. E., Ledbetter J. A., McGowan P., Linsley P. S. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell. 1992 Dec 24;71(7):1093–1102. doi: 10.1016/s0092-8674(05)80059-5. [DOI] [PubMed] [Google Scholar]
  4. Christianson S. W., Shultz L. D., Leiter E. H. Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD.NON-Thy-1a donors. Diabetes. 1993 Jan;42(1):44–55. doi: 10.2337/diab.42.1.44. [DOI] [PubMed] [Google Scholar]
  5. Danska J. S., Livingstone A. M., Paragas V., Ishihara T., Fathman C. G. The presumptive CDR3 regions of both T cell receptor alpha and beta chains determine T cell specificity for myoglobin peptides. J Exp Med. 1990 Jul 1;172(1):27–33. doi: 10.1084/jem.172.1.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Edouard P., Thivolet C., Bedossa P., Olivi M., Legrand B., Bendelac A., Bach J. F., Carnaud C. Evidence for a preferential V beta usage by the T cells which adoptively transfer diabetes in NOD mice. Eur J Immunol. 1993 Mar;23(3):727–733. doi: 10.1002/eji.1830230324. [DOI] [PubMed] [Google Scholar]
  7. Freeman G. J., Gray G. S., Gimmi C. D., Lombard D. B., Zhou L. J., White M., Fingeroth J. D., Gribben J. G., Nadler L. M. Structure, expression, and T cell costimulatory activity of the murine homologue of the human B lymphocyte activation antigen B7. J Exp Med. 1991 Sep 1;174(3):625–631. doi: 10.1084/jem.174.3.625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gimmi C. D., Freeman G. J., Gribben J. G., Gray G., Nadler L. M. Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6586–6590. doi: 10.1073/pnas.90.14.6586. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gimmi C. D., Freeman G. J., Gribben J. G., Sugita K., Freedman A. S., Morimoto C., Nadler L. M. B-cell surface antigen B7 provides a costimulatory signal that induces T cells to proliferate and secrete interleukin 2. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6575–6579. doi: 10.1073/pnas.88.15.6575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Harding F. A., Allison J. P. CD28-B7 interactions allow the induction of CD8+ cytotoxic T lymphocytes in the absence of exogenous help. J Exp Med. 1993 Jun 1;177(6):1791–1796. doi: 10.1084/jem.177.6.1791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Haskins K., McDuffie M. Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone. Science. 1990 Sep 21;249(4975):1433–1436. doi: 10.1126/science.2205920. [DOI] [PubMed] [Google Scholar]
  12. Hänninen A., Jalkanen S., Salmi M., Toikkanen S., Nikolakaros G., Simell O. Macrophages, T cell receptor usage, and endothelial cell activation in the pancreas at the onset of insulin-dependent diabetes mellitus. J Clin Invest. 1992 Nov;90(5):1901–1910. doi: 10.1172/JCI116067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ikegami H., Eisenbarth G. S., Hattori M. Major histocompatibility complex-linked diabetogenic gene of the nonobese diabetic mouse. Analysis of genomic DNA amplified by the polymerase chain reaction. J Clin Invest. 1990 Jan;85(1):18–24. doi: 10.1172/JCI114410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ikegami H., Kawaguchi Y., Ueda H., Fukuda M., Takakawa K., Fujioka Y., Fujisawa T., Uchida K., Ogihara T. MHC-linked diabetogenic gene of the NOD mouse: molecular mapping of the 3' boundary of the diabetogenic region. Biochem Biophys Res Commun. 1993 Apr 30;192(2):677–682. doi: 10.1006/bbrc.1993.1468. [DOI] [PubMed] [Google Scholar]
  15. Itoh N., Hanafusa T., Miyazaki A., Miyagawa J., Yamagata K., Yamamoto K., Waguri M., Imagawa A., Tamura S., Inada M. Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients. J Clin Invest. 1993 Nov;92(5):2313–2322. doi: 10.1172/JCI116835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Katz J., Benoist C., Mathis D. Major histocompatibility complex class I molecules are required for the development of insulitis in non-obese diabetic mice. Eur J Immunol. 1993 Dec;23(12):3358–3360. doi: 10.1002/eji.1830231244. [DOI] [PubMed] [Google Scholar]
  17. Koop B. F., Wilson R. K., Wang K., Vernooij B., Zallwer D., Kuo C. L., Seto D., Toda M., Hood L. Organization, structure, and function of 95 kb of DNA spanning the murine T-cell receptor C alpha/C delta region. Genomics. 1992 Aug;13(4):1209–1230. doi: 10.1016/0888-7543(92)90039-u. [DOI] [PubMed] [Google Scholar]
  18. Koulova L., Clark E. A., Shu G., Dupont B. The CD28 ligand B7/BB1 provides costimulatory signal for alloactivation of CD4+ T cells. J Exp Med. 1991 Mar 1;173(3):759–762. doi: 10.1084/jem.173.3.759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kwon B. S., Wakulchik M., Liu C. C., Persechini P. M., Trapani J. A., Haq A. K., Kim Y., Young J. D. The structure of the mouse lymphocyte pore-forming protein perforin. Biochem Biophys Res Commun. 1989 Jan 16;158(1):1–10. doi: 10.1016/s0006-291x(89)80168-8. [DOI] [PubMed] [Google Scholar]
  20. Linsley P. S., Brady W., Grosmaire L., Aruffo A., Damle N. K., Ledbetter J. A. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med. 1991 Mar 1;173(3):721–730. doi: 10.1084/jem.173.3.721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Linsley P. S., Ledbetter J. A. The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol. 1993;11:191–212. doi: 10.1146/annurev.iy.11.040193.001203. [DOI] [PubMed] [Google Scholar]
  22. Liu Y., Janeway C. A., Jr Cells that present both specific ligand and costimulatory activity are the most efficient inducers of clonal expansion of normal CD4 T cells. Proc Natl Acad Sci U S A. 1992 May 1;89(9):3845–3849. doi: 10.1073/pnas.89.9.3845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lund T., O'Reilly L., Hutchings P., Kanagawa O., Simpson E., Gravely R., Chandler P., Dyson J., Picard J. K., Edwards A. Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A beta-chain or normal I-E alpha-chain. Nature. 1990 Jun 21;345(6277):727–729. doi: 10.1038/345727a0. [DOI] [PubMed] [Google Scholar]
  24. McInerney M. F., Rath S., Janeway C. A., Jr Exclusive expression of MHC class II proteins on CD45+ cells in pancreatic islets of NOD mice. Diabetes. 1991 May;40(5):648–651. doi: 10.2337/diab.40.5.648. [DOI] [PubMed] [Google Scholar]
  25. Nagata M., Santamaria P., Kawamura T., Utsugi T., Yoon J. W. Evidence for the role of CD8+ cytotoxic T cells in the destruction of pancreatic beta-cells in nonobese diabetic mice. J Immunol. 1994 Feb 15;152(4):2042–2050. [PubMed] [Google Scholar]
  26. Nishimoto H., Kikutani H., Yamamura K., Kishimoto T. Prevention of autoimmune insulitis by expression of I-E molecules in NOD mice. 1987 Jul 30-Aug 5Nature. 328(6129):432–434. doi: 10.1038/328432a0. [DOI] [PubMed] [Google Scholar]
  27. O'Reilly L. A., Hutchings P. R., Crocker P. R., Simpson E., Lund T., Kioussis D., Takei F., Baird J., Cooke A. Characterization of pancreatic islet cell infiltrates in NOD mice: effect of cell transfer and transgene expression. Eur J Immunol. 1991 May;21(5):1171–1180. doi: 10.1002/eji.1830210512. [DOI] [PubMed] [Google Scholar]
  28. Prochazka M., Gaskins H. R., Shultz L. D., Leiter E. H. The nonobese diabetic scid mouse: model for spontaneous thymomagenesis associated with immunodeficiency. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3290–3294. doi: 10.1073/pnas.89.8.3290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ramarathinam L., Castle M., Wu Y., Liu Y. T cell costimulation by B7/BB1 induces CD8 T cell-dependent tumor rejection: an important role of B7/BB1 in the induction, recruitment, and effector function of antitumor T cells. J Exp Med. 1994 Apr 1;179(4):1205–1214. doi: 10.1084/jem.179.4.1205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Reich E. P., Sherwin R. S., Kanagawa O., Janeway C. A., Jr An explanation for the protective effect of the MHC class II I-E molecule in murine diabetes. Nature. 1989 Sep 28;341(6240):326–328. doi: 10.1038/341326a0. [DOI] [PubMed] [Google Scholar]
  31. Reiner S. L., Zheng S., Corry D. B., Locksley R. M. Constructing polycompetitor cDNAs for quantitative PCR. J Immunol Methods. 1993 Sep 27;165(1):37–46. doi: 10.1016/0022-1759(93)90104-f. [DOI] [PubMed] [Google Scholar]
  32. Rohane P. W., Shimada A., Kim D. T., Edwards C. T., Charlton B., Shultz L. D., Fathman C. G. Islet-infiltrating lymphocytes from prediabetic NOD mice rapidly transfer diabetes to NOD-scid/scid mice. Diabetes. 1995 May;44(5):550–554. doi: 10.2337/diab.44.5.550. [DOI] [PubMed] [Google Scholar]
  33. Santamaria P., Utsugi T., Park B. J., Averill N., Kawazu S., Yoon J. W. Beta-cell-cytotoxic CD8+ T cells from nonobese diabetic mice use highly homologous T cell receptor alpha-chain CDR3 sequences. J Immunol. 1995 Mar 1;154(5):2494–2503. [PubMed] [Google Scholar]
  34. Schwartz R. H. A cell culture model for T lymphocyte clonal anergy. Science. 1990 Jun 15;248(4961):1349–1356. doi: 10.1126/science.2113314. [DOI] [PubMed] [Google Scholar]
  35. Serreze D. V., Leiter E. H., Christianson G. J., Greiner D., Roopenian D. C. Major histocompatibility complex class I-deficient NOD-B2mnull mice are diabetes and insulitis resistant. Diabetes. 1994 Mar;43(3):505–509. doi: 10.2337/diab.43.3.505. [DOI] [PubMed] [Google Scholar]
  36. Serreze D. V., Leiter E. H. Genetic and pathogenic basis of autoimmune diabetes in NOD mice. Curr Opin Immunol. 1994 Dec;6(6):900–906. doi: 10.1016/0952-7915(94)90011-6. [DOI] [PubMed] [Google Scholar]
  37. Shimizu J., Kanagawa O., Unanue E. R. Presentation of beta-cell antigens to CD4+ and CD8+ T cells of non-obese diabetic mice. J Immunol. 1993 Aug 1;151(3):1723–1730. [PubMed] [Google Scholar]
  38. Sibley R. K., Sutherland D. E., Goetz F., Michael A. F. Recurrent diabetes mellitus in the pancreas iso- and allograft. A light and electron microscopic and immunohistochemical analysis of four cases. Lab Invest. 1985 Aug;53(2):132–144. [PubMed] [Google Scholar]
  39. Signore A., Pozzilli P., Gale E. A., Andreani D., Beverley P. C. The natural history of lymphocyte subsets infiltrating the pancreas of NOD mice. Diabetologia. 1989 May;32(5):282–289. doi: 10.1007/BF00265543. [DOI] [PubMed] [Google Scholar]
  40. Tan R., Teh S. J., Ledbetter J. A., Linsley P. S., Teh H. S. B7 costimulates proliferation of CD4-8+ T lymphocytes but is not required for the deletion of immature CD4+8+ thymocytes. J Immunol. 1992 Nov 15;149(10):3217–3224. [PubMed] [Google Scholar]
  41. Thompson C. B., Lindsten T., Ledbetter J. A., Kunkel S. L., Young H. A., Emerson S. G., Leiden J. M., June C. H. CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/cytokines. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1333–1337. doi: 10.1073/pnas.86.4.1333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Todd J. A., Aitman T. J., Cornall R. J., Ghosh S., Hall J. R., Hearne C. M., Knight A. M., Love J. M., McAleer M. A., Prins J. B. Genetic analysis of autoimmune type 1 diabetes mellitus in mice. Nature. 1991 Jun 13;351(6327):542–547. doi: 10.1038/351542a0. [DOI] [PubMed] [Google Scholar]
  43. Townsend S. E., Allison J. P. Tumor rejection after direct costimulation of CD8+ T cells by B7-transfected melanoma cells. Science. 1993 Jan 15;259(5093):368–370. doi: 10.1126/science.7678351. [DOI] [PubMed] [Google Scholar]
  44. Wang K., Klotz J. L., Kiser G., Bristol G., Hays E., Lai E., Gese E., Kronenberg M., Hood L. Organization of the V gene segments in mouse T-cell antigen receptor alpha/delta locus. Genomics. 1994 Apr;20(3):419–428. doi: 10.1006/geno.1994.1196. [DOI] [PubMed] [Google Scholar]
  45. Wicker L. S., Leiter E. H., Todd J. A., Renjilian R. J., Peterson E., Fischer P. A., Podolin P. L., Zijlstra M., Jaenisch R., Peterson L. B. Beta 2-microglobulin-deficient NOD mice do not develop insulitis or diabetes. Diabetes. 1994 Mar;43(3):500–504. doi: 10.2337/diab.43.3.500. [DOI] [PubMed] [Google Scholar]

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

RESOURCES