Amplification of Autoimmune Response through Induction of Dendritic Cell Maturation in Inflamed Tissues

Abstract

Dendritic cells (DCs) are essential in T cell-mediated destruction of insulin-producing ␤ cells in the islets of Langerhans in type 1 diabetes. In this study, we investigated T cell induction of intra-islet DC maturation during the progression of the disease in both autoimmune-prone NOD and resistant C57BL/6 mice. We demonstrated steady-state capture and retention of unprocessed ␤ cellderived proteins by semimature intra-islet DCs in both mouse strains. T cell-mediated intra-islet inflammation induced an increase in CD40 and CD80 expression and processing of captured Ag by resident DCs without inducing the expression of the p40 subunit of IL-12/23. Some of the CD40 high intra-islet DCs up-regulated CCR7, and a small number of CD40 high DCs bearing unprocessed islet Ags were detected in the pancreatic lymph nodes in mice with acute intra-islet inflammation, demonstrating that T cell-mediated tissue inflammation augments migration of mature resident DCs to draining lymph nodes. Our results identify an amplification loop during the progression of autoimmune diabetes, in which initial T cell infiltration leads to rapid maturation of intra-islet DCs, their migration to lymph nodes, and expanded priming of more autoreactive T cells. Therapeutic interventions that intercept this process may be effective at halting the progression of type 1 diabetes.

Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

“…*p<0.05 vs T cells co-cultured with autologous DCs; paired data mechanisms. DCs can bidirectionally promote either the priming and differentiation of self-reactive T cells or tolerance through the generation of Tregs or induction of effector T cell unresponsiveness [22][23][24][25]. Ex vivo manipulated tolerogenic DC-based therapies for animal models of autoimmune diseases have been reported.…”

“…This potential limiting effect could, nevertheless, inhibit an autoimmune amplification loop during the progression of type 1 diabetes. Indeed, in NOD mice, tissue inflammation augments DC maturation, CCR7 upregulation and migration to lymph nodes, where they amplify the ongoing immune response by promoting the priming of autoreactive T cells [25].…”

Beta cells transfer vesicles containing insulin to phagocytes for presentation to T cells

“…Importantly, when isolated they were strong antigen-presenting cells (APCs), particularly of insulin epitopes (5,13). Furthermore, an initial ultrastructural analysis showed dense-core secretory granules inside vacuoles of the islet phagocytes residing in the islets (13), and by immunofluorescence islet phagocytes were shown to contain products from the beta cells (5,13,14). Direct evidence of insulin peptides within the beta cells and in islet phagocytes was obtained using a monoclonal antibody that was exclusively reactive with an insulin B chain peptide segment and not with native insulin (5).…”

Targeted regulation of self-peptide presentation prevents type I diabetes in mice without disrupting general immunocompetence

“…Indeed, the activation of self-reactive T cell responses that ultimately lead to β cell destruction and T1D requires presentation of islet-derived antigens (Ags) by DCs (3,4). Additionally, DC Ag presentation is thought to drive disease amplification that maintains the autoimmune response and results in β cell destruction (5).…”