INTRATHYMIC TRANSPLANTATION OF ISLET ANTIGEN AFFECTS CD8(-CELLS RESULTING IN TOLERANCE TO AUTOIMMUNE IDDM() DIABETOGENIC T)

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. No rmally, 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 int o the thymus at the time of T-cell. maturation results in prevention o f IDDM in the multidose streptozotocin model of diabetes mellitus (MDS DM). Although both CD4(+) and CD8(+) T-cells are involved in the patho genesis of this disease, the cells affected by intrathymic transplanta tion of islets are unknown. In this study, we have identified which T- cell subsets are affected by intrathymic islet antigens. Streptozotoci n (STZ)-treated syngeneic islets were transplanted into the thymuses o f C57BL/KsJ mice, and CD4(+), CD8(+), or both subsets of cells were tr ansiently depleted with monoclonal antibodies (mAbs). After T-cell rep opulation, animals that had received intrathymic islets followed by an ti-CD8 mAb (P < 0.05) or both anti-CD4 and anti-CD8 mAbs (P < 0.01) bu t not anti-CD4 mAb alone were resistant to the development of autoimmu ne diabetes after five low doses of STZ. Insulitis was also reduced in mice receiving intrathymic islets and anti-CDS (P < 0.025) or both an ti-CD4 and anti-CD8 mAbs (P < 0.001). Treatment of islets with STZ bef ore intrathymic transplantation was needed to induce tolerance. When m ice that had been rendered tolerant to MDSDM by treatment with intrath ymic islets and anti-CD3 or anti-CD4 plus anti-CD8 mAbs received an ad optive 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 t hat the induction of tolerance after intrathymic transplantation of an tigen-bearing islets affects developing CD8(+) but not CD4(+) diabetog enic T-cells.