Breakdown in peripheral tolerance in type 1 diabetes in mice and humans

Abstract

Type 1 Diabetes (T1D), also called juvenile diabetes because of its classically early onset, is considered an autoimmune disease targeting the insulin-producing β cells in the pancreatic islets of Langerhans. T1D reflects a loss of tolerance to tissue self-antigens caused by defects in both central tolerance, which aims at eliminating potentially autoreactive lymphocytes developing in the thymus, and peripheral tolerance, which normally controls autoreactive T cells that escaped the thymus. Like in other autoimmune diseases, the mechanisms leading to T1D are multifactorial and depend on a complex combination of genetic, epigenetic, molecular, and cellular elements that result in the breakdown of peripheral tolerance. In this article, we discuss the contribution of these factors in the development of the autoimmune response targeting pancreatic islets in T1D and the therapeutic strategies currently being explored to correct these defects.

Figure 1.

Cellular and molecular components of tolerance versus autoimmunity. This figure schematically describes the major cell subsets involved in tolerogenic versus autoimmune conditions in the pancreatic LN and islets (see text for details). In tolerance (left panel), DCs express low amounts of self-antigen-MHC complexes and do not efficiently stimulate autoreactive T cells (designated as CD4⁺ Th1 for simplification but could also be autoreactive CD8⁺ T cells); Tregs efficiently suppress Teff; effector responses are skewed toward the protective Th2 subset; and intrinsic inhibitory molecules such as CTLA-4 and PD-1 control Teff in the LN and tissue. In autoimmunity (right panel), DCs are functionally mature with high levels of self-antigen-MHC complexes, costimulatory molecules (not shown) and proinflammatory cytokines such as IL-12; DC function is initiated and/or amplified by the release of self-antigens following tissue damage and potentially the influence of the gut; Teff escape Treg-mediated immunoregulation because of both defective numbers, survival and/or function of Tregs and resistance of Teff to suppression; effector responses are predominated by proinflammatory Th1 cells; Teff are not efficiently controlled by immunoregulatory molecules such as CTLA-4 and PD-1. The autoimmune process ultimately results in destruction of pancreatic islets and deficient insulin production.

Figure 2.

Role of the IL-2 pathway and the Teff/Treg balance in the tissue. This figure depicts how the balance of Teff and Tregs and their complex interactions, notably the IL-2 pathway, results in destruction or protection of pancreatic islets (see text for details). A magnified view of the outcome of IL-2 signaling in Tregs is shown at the bottom. In islets or individuals in which protection is dominant (left panel), the Teff/Treg ratio is skewed toward regulation; Teff secrete significant amounts of IL-2; IL-2 binds to the IL-2 receptor, expressed at high levels on Tregs, which triggers a robust IL-2 signaling, including high levels of STAT5 phosphorylation; this, in turn, ultimately results in the transcription of many IL-2 dependent genes, including Foxp3, which are important to maintain their survival at the tissue site. In individuals genetically susceptible to diabetes (right panel), the survival of Tregs in the islets is compromised and they cannot control the Teff pathogenic response; the half-life or levels of secretion of IL-2 by Teff is deficient; IL-2 signaling is reduced because of lower expression of the IL-2 receptor and/or lower STAT5 phosphorylation; this results in altered transcription of IL-2-dependent genes and poor survival of Tregs in the islets.