Abstract
T-cell responses to insulin and its precursor proinsulin are central to islet autoimmunity in humans and non-obese diabetic (NOD) mice that spontaneously develop autoimmune diabetes. Mice have two proinsulin genes proinsulin -1 and 2 that are differentially expressed, with predominant proinsulin-2 expression in the thymus and proinsulin-1 in islet beta-cells. In contrast to proinsulin-2, proinsulin-1 knockout NOD mice are protected from autoimmune diabetes. This indicates that proinsulin-1 epitopes in beta-cells maybe preferentially targeted by autoreactive T cells. To study the contribution of proinsulin-1 reactive T cells in autoimmune diabetes, we generated transgenic NOD mice with tetracycline-regulated expression of proinsulin-1 in antigen presenting cells (TIP-1 mice) with an aim to induce immune tolerance. TIP-1 mice displayed a significantly reduced incidence of spontaneous diabetes, which was associated with reduced severity of insulitis and insulin autoantibody development. Antigen experienced proinsulin specific T cells were significantly reduced in in TIP-1 mice indicating immune tolerance. Moreover, T cells from TIP-1 mice expressing proinsulin-1 transferred diabetes at a significantly reduced frequency. However, proinsulin-1 expression in APCs had minimal impact on the immune responses to the downstream antigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) and did not prevent diabetes in NOD 8.3 mice with a pre-existing repertoire of IGRP reactive T cells. Thus, boosting immune tolerance to proinsulin-1 partially prevents islet-autoimmunity. This study further extends the previously established role of proinsulin-1 epitopes in autoimmune diabetes in NOD mice.
Highlights
Recognition of proinsulin by the immune system is a major determinant in the pathogenesis of autoimmune diabetes in both humans and non-obese diabetic (NOD) mice [1, 2]
We examined the expression of Foxp3 on insulin B:9-23 specific CD4+ T cells in peripheral lymphoid organs (PLO) of TIP-1 mice and nontransgenic controls and did not observe any significant differences (Figure S2A, B), In addition we examined the frequency of Foxp3+ CD4+ Tregs in the thymus and pancreatic lymph node (PLN)
The main findings of this study are 1) TIP-1 mice expressing proinsulin 1 (PIns1) in the antigen presenting cells (APCs) show significantly reduced incidence of diabetes, which is associated with reduced insulitis and insulin autoantibody (IAA) expression
Summary
Recognition of proinsulin by the immune system is a major determinant in the pathogenesis of autoimmune diabetes in both humans and non-obese diabetic (NOD) mice [1, 2]. Immune responses to native insulin peptides, in particular the B chain amino acids 9-23 (Ins B:9-23), are essential for autoimmune diabetes in NOD mice [10, 11]. The two proinsulin isoforms differ by a single amino acid in the B: 9-23 region (PIns: B9 proline, PIns: B9 serine) and strong crossreactivity of T cells for the Ins B: 9-23 epitope in both proinsulin molecules has been reported [12]. NOD mice lacking Ins gene develop accelerated diabetes, ascribed to loss of central tolerance to insulin peptides; development of insulin autoantibodies (IAA) in Ins2 -/- mice suggests that immune responses against PIns epitopes are intact [15]. Immunogenic epitopes in the PIns molecule have been reported [18], and T cells recognizing PIns amino acids 47-64 in the C-peptide region induce diabetes in NOD.SCID recipients [19]. Epitopes in PIns molecule may contribute to islet autoimmunity
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