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

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.