Endocardial cells function as antigen-presenting cells to promote zebrafish heart regeneration

In contrast to adult mammals, adult zebrafish are able to fully regenerate injured cardiac tissue, and this regeneration process requires an adequate and tightly controlled immune response. However, which immune aspects drive particular aspects of the regenerative response are unclear. Here, we report the participation and requirement of the antigen presentation-adaptive immunity axis during zebrafish cardiac regeneration. We found that, in addition to immune cells, endocardial cells start expressing antigen presentation genes following the initial innate immune response. Consistent with this finding, we observed that helper T cells, a.k.a. Cd4+ T cells, are closely associated with phosphoERK+ (pERK+) (i.e., activated) endocardial cells at these stages. We inactivated major histocompatibility complex (MHC) class II antigen presentation by generating cd74a; cd74b double mutants, which display a defective immune response. In these mutants, both Cd4+ T cells and pERK+ endocardial cells fail to efficiently infiltrate the injured tissue. Notably, this model of compromised antigen presentation exhibits additional defects in cardiac regeneration including reduced cardiomyocyte dedifferentiation and proliferation. Altogether, these findings reveal a necessary role for antigen presentation during zebrafish cardiac regeneration and point to an immune crosstalk between T cells and endocardial cells, thereby further establishing a link between the adaptive immune response and tissue regeneration. Comparative gene expression analysis between wild-type zebrafish cryoinjured ventricles (7 days post-cryoinjury) and cd74a;cd74b mutant ventricles (duplicates).