Paraoxonase 1 knockout rats have impaired T cell development at the CD4/CD8 double-negative to double-positive transition stage

Paraoxonase 1 (PON1) is a high-density lipoprotein-associated enzyme that performs multiple physiological activities. Previous studies suggest that PON1 plays an anti-inflammatory role in the cardiovascular system, although its roles in hematopoiesis and adaptive immunity have not been clarified. To investigate the impact of PON1 on the immune system, we generated PON1-knockout (PON1(−/−)) rats using the CRISPR/Cas9 system. The thymus was smaller in PON1(−/−) rats than that in wild-type (PON1(+/+)) rats. Furthermore, analysis of thymocyte development revealed diminished total T cell numbers and a decrease in CD4(+), CD8(+) and double-positive T cells in peripheral blood and thymus from PON1(−/−) rats. This may be due to a block in the transition of T cells from the double-negative to the double-positive stage. We also showed that the activation of p38 MAPK phosphorylation contributed to the increased apoptosis and defective T cell development in PON(−/−) rats. Therefore, our results indicate that PON1 functions as a novel regulator of T cell development.