IL ‐10 producing type 2 innate lymphoid cells prolong islet allograft survival

Abstract

Type 2 innate lymphoid cells (ILC2s) are a subset of ILCs with critical roles in immunoregulation. However, the possible role of ILC2s as immunotherapy against allograft rejection remains unclear. Here, we show that IL‐33 significantly prolonged islet allograft survival. IL‐33‐treated mice had elevated numbers of ILC2s and regulatory T cells (Tregs). Depletion of Tregs partially abolished the protective effect of IL‐33 on allograft survival, and additional ILC2 depletion in Treg‐depleted DEREG mice completely abolished the protective effects of IL‐33, indicating that ILC2s play critical roles in IL‐33‐mediated islet graft protection. Two subsets of ILC2s were identified in islet allografts of IL‐33‐treated mice: IL‐10 producing ILC2s (ILC210) and non‐IL‐10 producing ILC2s (non‐ILC10). Intravenous transfer of ILC210 cells, but not non‐ILC10, prolonged islet allograft survival in an IL‐10‐dependent manner. Locally transferred ILC210 cells led to long‐term islet graft survival, suggesting that ILC210 cells are required within the allograft for maximal suppressive effect and graft protection. This study has uncovered a major protective role of ILC210 in islet transplantation which could be potentiated as a therapeutic strategy.

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“…To visualize MMP inhibition, samples were treated with carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP, abcam, ab120081) prepared in culture media at 100 μM concentration for 15 min at 37 °C, 5% CO 2 in the dark. Many research groups have used this high concentration to eliminate the MMP and JC-1 staining to serve as a depolarization control for JC-1, as well as provide an indication of cellular response to FCCP 43 – 47 . After FCCP treatment, samples were incubated in JC-1 staining solution for 30 min and 2 drops per mL of NucBlue Live ReadyProbes Reagent (Invitrogen, R37605) for 20 min at 37 °C, 5% CO 2 in the dark.…”

IL-10-Producing ILCs: Molecular Mechanisms and Disease Relevance

“…Two subsets of ILC2s were identified in islet allografts of IL-33-treated mice: IL-10-producing ILC2s (termed ILC2 10 ) and non-IL-10 producing ILC2s (termed non-ILC2 10 ). Intravenous transfer of ILC2 10 , but non-ILC 10 , markedly prolonged islet allograft survival in an IL-10-dependent manner ( 96 ).…”

Stem Cell-Based Clinical Trials for Diabetes Mellitus

“…Immune suppression in general remains critical to prevent rejection of the graft. A combination of induction (administered only at the time of transplant) and maintenance (administered for long-term regime) immune suppressive agents are necessary for graft survival, and despite the advancements in the immunosuppressive regimen (22), the majority of the patients still require additional islet infusions (10 th Annual Report, CITR).…”