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