Zebrafish T cells mediate organ-specific regenerative programs

SP Hui, DZ Sheng, K Sugimoto, A Gonzalez-Rajal and K Kikuchi

Victor Chang Cardiac Research Institute

In mammals, T cells play major roles in response to tissue injury and subsequent repair through diverse functions, including the promotion of tissue growth and scarring. Although the adaptive immune system is highly developed in regenerative vertebrates such as salamanders and fish, little is known about the contributions of T cells to scarless regeneration in these animals. Here, we demonstrate that successful tissue regeneration in the teleost zebrafish requires a T-cell subset that has the capacity to produce tissue-specific growth factors. Using a transgenic reporter strain, we found that T cells infiltrated damaged tissues and closely associated with regenerating parenchymal cells (e.g. new neurons, proliferating cardiomyocytes). Inducible genetic ablation of T cells was associated with elevated inflammation and severely impaired spinal cord and heart regeneration as well as significantly reduced neurogenesis and cardiomyocyte proliferation. We found that spinal cord-infiltrating T cells specifically synthesised neurogenic factors, whereas heart-infiltrating T cells synthesised cardiomyocyte mitogens. Furthermore, neurogenic and cardiogenic factor administrations restored the neurogenesis and cardiomyocyte proliferation defects associated with T cell depletion. Thus, zebrafish T cells elaborate an organ-specific secretory phenotype and directly enhance spinal cord and cardiac regeneration by promoting neurogenesis and cardiomyocyte proliferation, respectively. These findings extend our understanding of the immunological regulation of organ regeneration and suggest T cell-mediated regenerative therapies for the treatment of spinal cord and cardiac damage in humans.