Project Summary/Abstract The neonatal mouse heart possesses a remarkable ability to regenerate following injury and this cardiac regeneration is closely accompanied by robust activation of the immune system. Studies in the last decade have focused on the role of innate immunity during neonatal heart regeneration, and have established the necessary roles for macrophages in the repair and regeneration processes following myocardial infarction (MI). However, macrophages alone are not sufficient to drive neonatal regeneration, as neonatal mice lacking adaptive immunity but retaining innate immunity cannot regenerate. This result strongly suggests that other immune cells such as those involved in adaptive immunity also play a role in neonatal heart regeneration. In this project, we aim to explore the role of adaptive immunity, in particular the CD4+ T helper 2 (Th2) cell-mediated inflammatory response as a bridge between adaptive and innate immune signaling pathways that mediate neonatal cardiomyocyte (CM) proliferation in response to injury. Our preliminary results revealed that the Th2 cell secreted cytokine interleukin 4 (IL-4) is strongly upregulated in neonatal day 1 mouse hearts after MI and can promote CM proliferation. Its receptor IL-4ra is highly expressed in the proliferating CM population. We hypothesize that the Th2 cell-mediated IL-4 signaling promotes CM proliferation and macrophage transformation, as well as generating the cardiotropic factor CCL24 as a critical cytokine pathway in neonatal heart regeneration. Understanding how immune cells participate in neonatal heart regeneration will enlighten the development of potential therapeutics to promote adult heart repair and regeneration in humans.