Prevention of murine autoimmune diabetes by CCL22-mediated Treg recruitment to the pancreatic islets
Joel Montane, … , Rusung Tan, C. Bruce Verchere
Joel Montane, … , Rusung Tan, C. Bruce Verchere
Published August 1, 2011; First published July 1, 2011
Citation Information: J Clin Invest. 2011;121(8):3024-3028. https://doi.org/10.1172/JCI43048.
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Category: Brief Report

Prevention of murine autoimmune diabetes by CCL22-mediated Treg recruitment to the pancreatic islets

Abstract

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.

Authors

Joel Montane, Loraine Bischoff, Galina Soukhatcheva, Derek L. Dai, Gijs Hardenberg, Megan K. Levings, Paul C. Orban, Timothy J. Kieffer, Rusung Tan, C. Bruce Verchere

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Figure 2

CCL22 expression recruits Tregs to pancreatic islets and reduces autoimmune response.

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CCL22 expression recruits Tregs to pancreatic islets and reduces autoimm...
(A, B, and D–F) Flow cytometric analysis of cells from CCL22-NOD and control mice. (A) The percentage of CD4+ cells that are FoxP3+ in pancreata of CCL22-NOD mice was not significantly elevated compared with that of PBS-NOD mice at 15 days but significantly increased by 1 month and further increased at 3 months after injection. (B) The absolute number of CD4+Foxp3+ cells was not significantly different at 15 days but was higher in pancreata of CCL22-NOD mice compared with that in PBS-NOD mice 1 month after injection. (C) In CCL22-NOD mice, injection of anti-CD25 antibody resulted in more rapid and frequent diabetes development than injection of isotype-matched IgG (CCL22-NOD plus anti-CD25 vs. CCL22-NOD plus IgG; P = 0.01) and was not significantly different from that in NOD mice that received anti-CD25 antibody alone or with PBS. (D) Increased frequency of TGF-β+ cells among CD4+ cells in CCL22-NOD mouse pancreata (3 months) and PLNs (1 month). (E) Decreased frequency of CD8+IFN-γ+ cells in pancreata from CCL22-NOD mice at 1 and 3 months after injection compared with that of PBS-NOD mice at 1 month. (F) The frequency of IGRP- (n = 7) and insulin (INS)- (n = 5) specific CD8+ T cells was lower in CCL22-NOD mice in peripheral blood 15 days and 2 months after injection. The frequency of total CD8+ cells in the blood was not significantly different among CCL22-NOD and control groups (not shown). *P < 0.05, **P < 0.01, ***P < 0.001 versus PBS.