Type 1 diabetes is characterized by destruction of insulin-producing β cells in the pancreatic islets by effector T cells. Tregs, defined by the markers CD4 and FoxP3, regulate immune responses by suppressing effector T cells and are recruited to sites of action by the chemokine CCL22. Here, we demonstrate that production of CCL22 in islets after intrapancreatic duct injection of double-stranded adeno-associated virus encoding CCL22 recruits endogenous Tregs to the islets and confers long-term protection from autoimmune diabetes in NOD mice. In addition, adenoviral expression of CCL22 in syngeneic islet transplants in diabetic NOD recipients prevented β cell destruction by autoreactive T cells and thereby delayed recurrence of diabetes. CCL22 expression increased the frequency of Tregs, produced higher levels of TGF-β in the CD4 + T cell population near islets, and decreased the frequency of circulating autoreactive CD8 + T cells and CD8 + IFN-γ-producing T cells. The protective effect of CCL22 was abrogated by depletion of Tregs with a CD25-specific antibody. Our results indicate that islet expression of CCL22 recruits Tregs and attenuates autoimmune destruction of β cells. CCL22-mediated recruitment of Tregs to islets may be a novel therapeutic strategy for type 1 diabetes.

Material Supplementary 2.DC1http://www.jimmunol.org/content/suppl/2010/07/16/jimmunol.100087

Autoimmune destruction of insulin-producing β cells in type 1 diabetes and islet transplantation involves a variety of immune pathways but is primarily mediated by self-reactive T cells. Chemokines can modulate local immune responses in inflammation and tumors by recruiting immune cells. We have reported that expression of the chemokine CCL22 in pancreatic β cells in the NOD mouse prevents autoimmune attack by recruiting T regulatory cells (Tregs), protecting mice from diabetes. In this study we show that invariant NKT cells are also recruited to CCL22-expressing islet transplants and are required for CCL22-mediated protection from autoimmunity. Moreover, CCL22 induces an influx of plasmacytoid dendritic cells, which correlates with higher levels of IDO in CCL22-expressing islet grafts. In addition to its chemotactic properties, we found that CCL22 activates Tregs and promotes their ability to induce expression of IDO by dendritic cells. Islet CCL22 expression thus produces a tolerogenic milieu through the interplay of Tregs, invariant NKT cells, and plasmacytoid dendritic cells, which results in suppression of effector T cell responses and protection of β cells. The immunomodulatory properties of CCL22 could be harnessed for prevention of graft rejection and type 1 diabetes as well as other autoimmune disorders.