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IDDM results from the destruction of pancreatic beta-cells by autoreactive T-cells that appear to avoid deletion early in development, possibly due to improper interaction with antigen-presenting cells (APCs) resident in the thymus or periphery. In the nonobese diabetic (NOD) mouse, there exists a defect in APC function characterized by its failure to fully mature upon stimulation. The NOD mouse thus provides an excellent model for the investigation of APC dysfunction and development and how these relate to the incidence of autoimmune diabetes. We initiated studies of APC function in the NOD mouse with respect to antigen processing and presentation, using a well-characterized antigen hen egg lysozyme (HEL) and comparing it with the closely related, major histocompatibility complex (MHC) (I-Ag7) identical, diabetes-resistant mouse strain NOR. Proliferation assays comparing NOD and NOR HEL-specific T-cells demonstrated that the T-cell proliferation response of the NOD mouse to both native and denatured forms of the antigen is lower than that of NOR. When crisscross proliferation experiments were conducted using purified T-cells and irradiated spleen cells as APCs from both strains, the results demonstrated that the defect in proliferation resided in the APC compartment of activation. The levels of intracellular glutathione (GSH) were compared in splenic macrophages from NOD and NOR mice; it was found that on antigenic stimulation, NOR macrophages produced significantly more intracellular GSH than did NOD macrophages, even under hyperglycemic (50 mmol/l glucose) conditions. The lower amount of GSH seen in the NOD may result in less efficient processing of antigen, and subsequently, lower levels of T-cell activation.

SUMMARY:Islet-specific T cells are essential in the development of type I diabetes. The role of non-lymphoid cells is relatively unclear, although infiltration of dendritic cells and macrophages is the first sign of islet autoimmunity in diabetes-prone nonobese diabetic (NOD) mice. BDC2.5 is one of the autoreactive T cell clones isolated from NOD mice. Transfer of BDC2.5 T cells into young NOD mice accelerates diabetes development, whereas transgenic expression of the BDC2.5 T cell receptor on NOD T cells (BDC2.5 TCR-Tg NOD) markedly reduces diabetes development. We show that, although the same antigen-specificity is involved, both models differ significantly in insulitis. BDC2.5 TCR-Tg NOD mice develop an extensive, but non-aggressive, peri-insulitis by 3 weeks of age. In these large peri-islet infiltrates, resembling secondary lymphoid tissue, BM8 ϩ macrophages (M) are virtually absent. In contrast, BDC2.5 T cell clone transfer results in an aggressive insulitis with small infiltrates, but relatively large numbers of BM8 ϩ M. Infiltration of BM8 ϩ M therefore correlates with islet destruction. This is, however, not observed for all M; Monts-4 ϩ M follow a reverse pattern and are present in higher numbers in BDC2.5 TCR-Tg than in transferred mice. ER-MP23 ϩ M are reduced in both transferred and transgenic mice compared with wild-type NOD. Thus, this study underlines and extends previous data suggesting that M are implicated in both early and late phases in diabetes development. Furthermore, our data imply that subsets of non-lymphoid cells have different roles in diabetes development. It is, therefore, important to recognize this heterogeneity when interpreting both in vivo and in vitro studies concerning non-lymphoid cells in diabetes. (Lab Invest 2000, 80:23-30).

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