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. 2015 Apr 1;194(7):3054-64.
doi: 10.4049/jimmunol.1400567. Epub 2015 Mar 4.

Cellular mechanisms of CCL22-mediated attenuation of autoimmune diabetes

Loraine Bischoff  1 , Sigrid Alvarez  1 , Derek L Dai  1 , Galina Soukhatcheva  1 , Paul C Orban  1 , C Bruce Verchere  2
Affiliations

Cellular mechanisms of CCL22-mediated attenuation of autoimmune diabetes

Loraine Bischoff et al. J Immunol. .

Abstract

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.

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