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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 July 1, 2011
Citation Information: J Clin Invest. 2011;121(8):3024-3028. https://doi.org/10.1172/JCI43048.
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Brief Report

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

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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 3

CCL22 expression prevents recurrent autoimmunity in NOD mice after syngeneic islet transplantation.

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CCL22 expression prevents recurrent autoimmunity in NOD mice after synge...
(A) Diabetic NOD mice were transplanted with Ad-CCL22 (n = 9), Ad-LacZ (n = 6), or untreated islets as controls (n = 5). Kaplan-Meier survival curves were derived from blood glucose data and compared using the log-rank test (P < 0.01 versus untreated and LacZ). (B) Flow cytometric analysis of draining renal lymph nodes (rLNs) and islet grafts of CD4+FoxP3+ cells (CCL22, n = 7; LacZ, n = 3) 10 days after transplantation. ***P < 0.001. (C) The ratio of CD4+FoxP3+ Tregs to CD4+ FoxP3– effector cells (Treg/CD4eff ratio) was determined in the grafts and renal lymph nodes of CCL22 (n = 15) and LacZ (n = 6) recipients 10 days after transplantation. **P < 0.01. (D) Detection of IGRP-specific CD8+ T cells in islet grafts and renal lymph nodes from recipients of CCL22-expressing (n = 7) and LacZ-expressing (n = 2) grafts. P = NS. (E) Depletion of Tregs in recipients of CCL22-expressing grafts using anti-CD25 antibody (anti-CD25, n = 7; IgG, n = 6). Survival curves were compared using the log-rank test. P = 0.01.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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