Within and beyond immunomodulatory strategies against autoimmune diabetes : antigen-specific tolerance and endothelial regeneration

Abstract

Type 1 diabetes (T1D) is a chronic disorder in which the cells of the immune system mediate selective destruction of the insulin-producing [beta]-cells in the islets of Langerhans in the pancreas. CD4+ effector T cells, including Th1 and Th17 cells, are crucial mediators during disease development. Therefore, therapeutic strategies against T1D should target both T cell subtypes. The mechanisms underlying the control of Th1 cells are well-defined, but those operating modulation of Th17 cells remain largely unknown due to the fact that Th17 cells are plastic and can drive the disease as convertible (Th17 to Th1) or stable T cells. To overcome these limitations, a tolerance induction model was developed to analyze the mechanisms underlying modulation of plastic Th17 cells. Indeed, upon induction of tolerance, convertible (Th17 to Th1) cells displayed downregulation of the chemokine receptor CXCR3 that was associated with diminished T-bet expression, leading to retention of the cells in the spleen and inhibition of trafficking to the pancreas. In contrast, stable Th17 cells downregulated RORγt but increased FasL expression and died by apoptosis under the same antigen-specific tolerance. Thus, the final signature transcription factor shapes the mechanism of tolerance in plastic Th17 cells. These findings suggest that effective strategies against T1D will require regimens that could drive both mechanisms of tolerance to overcome the disease. A core feature of autoimmune diabetes is the loss of the majority of insulin-producing [beta] cells. Therefore, reversal of overt T1D requires restoration of [beta]-cell mass in addition to effective control of islet inflammation. It has been established that [beta]-cell turnover relies on self-replication of pre-existing [beta]-cells; however, the diabetic state is tightly associated with a striking decrease of the islet endothelial cells, leading to poor [beta]-cell survival and function. Given that the endothelial progenitor cells (EPCs) reside in the bone marrow and the