Trp53 negatively regulates autoimmunity via the STAT3‐Th17 axis

ABSTRACT Emerging evidence suggests that the tumor suppressor p53 is also a crucial regulator for many physiological processes. Previous observations indicate that p53 suppresses inflammation by inhibiting inflammatory antigen‐presenting cells. To investigate the potential role of p53 in autoimmune effector T cells, we generated p53null CD45.1 mice by crossing p53null CD45.2 and CD45.1 mice. We demonstrate that p53null CD45.1 mice spontaneously developed autoimmunity, with a significant increase in IL‐17‐producing Th17 effectors in their lymph nodes (4.7±1.0%) compared to the age‐matched counterparts (1.9±0.8% for p53null CD45.2, 1.1 ±0.2% for CD45.1, and 0.5±0.1% for CD45.2mice). Likewise, p53null CD45.1 mice possess highly elevated serum levels of inflammatory cytokines IL17 and IL6. This enhanced Th17 response results largely from an increased sensitivity of p53null CD45.1 T cells to IL6‐induced STAT3 phosphorylation. Administration of STAT3 inhibitor S31‐201 (IC50 of 38.0±7.2 μM for IL6‐induced STAT3 phosphorylation), but not PBS control, to p53null CD45.1 mice suppressed Th17 effectors and alleviated autoimmune pathology. This is the first report revealing that p53 activity in T cells suppresses autoimmunity by controlling Th17 effectors. This study suggests that p53 serves as a guardian of immunological functions and that the p53‐STAT3‐Th17 axis might be a therapeutic target for autoimmunity.—Zhang, S., Zheng, M., Kibe, R., Huang, Y., Marrero, L., Warren, S., Zieske, A. W., Iwakuma, T., Kolls, J. K., Cui, Y. Trp53 negatively regulates autoimmunity via the STAT3‐Th17 axis. FASEB J. 25, 2387–2398 (2011). www.fasebj.org