Fate mapping reveals a prenatal-to-neonatal wave of ILC2s with a history of Cd3g expression

Group 2 innate lymphoid cells (ILC2s) are thought to develop in the bone marrow and fetal liver. However, increasing evidence supports the presence of thymic ILC2s in mice and humans. In this study, we introduce a novel fate-mapping mouse model designed to track thymic ILC2s in peripheral tissues. Thymic ILC2s are labeled by ZsGreen, whose expression is induced by Cd3giCre. While they are present in the thymus and peripheral tissues, they are not found in the bone marrow. These cells are predominantly abundant during the neonatal stage, when the intense lung alveolarization and tissue remodeling occur. RNA sequencing revealed elevated expression of cytokine genes Il13 and Il4, as well as Klrg1, in these cells. They also harbor TCR gene rearrangements, suggesting common developmental pathways with T cells. Furthermore, we demonstrate that neonatal ILC2s play a critical role in macrophage polarization in a naphthalene-induced lung injury model. These findings help explore the differences between pediatric and adult immunity and future therapeutic strategies.