Dendritic Cells and Immunoregulation in the Pathogenesis and Prevention of Type 1 Diabetes

Abstract

Dendritic cells govern the outcome of an immune response toward either tolerance or autoimmunity. Recent evidence has demonstrated that central tolerance is associated with relatively immature dendritic cells or quiescent mature dendritic cells that present self-antigens to autoreactive T cells, thereby silencing their autoreactive potential and/or activating regulatory T cells. Conversely, activated mature dendritic cells that have been instructed to become potent T cell stimulators by adjuvants or pathogens are capable of converting tolerance to immune activation. In combination with genetic and environmental influences, such mature dendritic cells are capable of orchestrating autoimmune responses. To explore the function of dendritic cells in type 1 diabetes, the authors evaluated peripheral dendritic cells from both patients with type 1 diabetes and the nonobese diabetic (NOD) mouse model that shares a pathologically analogous disease process. Dendritic cells in NOD mice are phenotypically comparable to dendritic cells from autoimmune-resistant controls with respect to expression of differentiation molecules. However, in response to maturation stimuli, such cells confer heightened activation of T cells and excessive production of pro-inflammatory cytokines. These findings highlight a putative contribution of unabated dendritic cell activation to the loss of self-tolerance and to chronic, self- directed responses that define type 1 diabetes. Moreover, effective manipulation of dendritic cell activation state pro- vides a promising avenue for regulating autoimmunity. Using a novel self-derived peptide that programs dendritic cell maturation and activation from monocytic precursors, the authors demonstrated suppression of autoreactivity in the NOD mouse model of type 1 diabetes. Collectively, these data are consistent with a model in which dendritic cells at different maturation and activation states regulate peripheral tolerance vs. autoimmunity