Intrathymic Transplantation of Islet Antigen Affects CD8+ Diabetogenic T-Cells Resulting in Tolerance to Autoimmune IDDM

  1. Kevan C Herold
  1. Departments of Medicine, The University of Chicago Chicago, Illinois
  2. Departments of Pediatrics, The University of Chicago Chicago, Illinois
  3. Committee on Immunology, The University of Chicago Chicago, Illinois
  4. The University of Chicago, and the Department of Surgery, Northwestern University Chicago, Illinois
  1. Address correspondence and reprint requests to Dr. Kevan C. Herold, Department of Medicine, M. C. 1027, The University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637.

Abstract

The acquisition of T-cell tolerance in the thymus is limited to those antigens expressed in the thymus at the time of T-cell development. Normally, islet antigens that are involved in insulin-dependent diabetes mellitus (IDDM) are not present in the thymus, but we have previously shown that transplantation of islets expressing relevant antigens into the thymus at the time of T-cell maturation results in prevention of IDDM in the multidose streptozotocin model of diabetes mellitus (MDSDM). Although both CD4+ and CD8+ T-cells are involved in the pathogenesis of this disease, the cells affected by intrathymic transplantation of islets are unknown. In this study, we have identified which T-cell subsets are affected by intrathymic islet antigens. Streptozotocin (STZ)-treated syngeneic islets were transplanted into the thymuses of C57BL/KsJ mice, and CD4+, CD8+, or both subsets of cells were transiently depleted with monoclonal antibodies (mAbs). After T-cell repopulation, animals that had received intrathymic islets followed by anti-CD8 mAb (P < 0.05) or both anti-CD4 and anti-CD8 mAbs (P < 0.01) but not anti-CD4 mAb alone were resistant to the development of autoimmune diabetes after five low doses of STZ. Insulitis was also reduced in mice receiving intrathymic islets and anti-CD8 (P < 0.025) or both anti-CD4 and anti-CD8 mAbs (P < 0.001). Treatment of islets with STZ before intrathymic transplantation was needed to induce tolerance. When mice that had been rendered tolerant to MDSDM by treatment with intrathymic islets and anti-CD3 or antl-CD4 plus anti-CD8 mAbs received an adoptive transfer of spleen cells from normal donor mice depleted of CD4+ but not CD8+ cells, susceptibility to diabetes was restored and hyperglycemia (P = 0.02) as well as insulitis developed. We conclude that the induction of tolerance after intrathymic transplantation of antigen-bearing islets affects developing CD8+ but not CD4+ diabetogenic T-cells.

  • Received October 5, 1994.
  • Revision received March 29, 1995.
  • Accepted March 29, 1995.
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