Abstract P3073: Interleukin-2 Receptor Gamma Signaling Is Required For The Regenerative Adaptive Immune Response In The Adult Zebrafish Heart

Abstract

Ischemic heart disease remains a leading cause of death worldwide. Unlike adult mammals, zebrafish have the ability to fully regenerate their heart after injury through processes including epicardium and endocardium activation, coronary revascularization, cardiomyocyte dedifferentiation and proliferation, and scar resolution. Immune cells are critical to remove damaged tissue, sustain repair and initiate regeneration after injury. Our previous data show that blocking antigen presentation impairs cardiac regeneration, pointing at a role for the adaptive immune system during this process. However, the molecular mechanisms underlying a pro-regenerative adaptive immune response remain largely unknown. Based on bulk transcriptomics, single-cell transcriptomics, and qPCR data, we have identified il2rga ( interleukin-2 receptor gamma a ) and jak3 ( janus kinase 3) as potential regulators of the adaptive immune response during cardiac regeneration. We indeed found that il2rga mutants exhibit a reduced expression of T-cell markers, as well as impaired cardiac regeneration, as observed by decreased cardiomyocyte dedifferentiation and proliferation, and defective scar resolution. In addition, il2rga mutants display decreased expression of pro-regenerative factors (e.g., igf1, ngfb, nrg1, pdgfaa, tgfb2, vegfc ). Similarly, loss of Jak3, which functions downstream of Il2rga, also leads to reduced cardiomyocyte dedifferentiation and proliferation, as well as impaired endocardium activation. Bulk transcriptomics further shows the downregulation of key genes involved in the adaptive immune response in il2rga mutants. Specifically, we found that il13 , a recently described cardiomyocyte cell cycle regulator and T helper 2 (Th2) cytokine, is strongly downregulated upon the loss of il2rga . Altogether, our findings reveal the crucial role of Il2rga/Jak3 signaling during cardiac regeneration, thereby opening new avenues to identify and understand the adaptive immune mechanisms capable of sustaining regenerative responses post-cardiac injury.