Emerging evidence suggests that the tumor suppressor p53 is also a crucial regulatory factor for many physiological processes. Previous observations indicate that p53 negatively regulates inflammation via suppressing inflammatory cytokine production by antigen presenting cells. However, the role of p53 in regulating autoimmune effector T cells, such as IL-17 producing Th17 cells, is largely unknown. Here, we demonstrate that p53nullCD45.1 mice spontaneously develop autoimmunity associated with a significant increase in Th17 cells in their lymphoid and pathological tissues as well as elevated levels of inflammatory cytokines IL-6 and IL-17 in serum. This increase in Th17 response results largely from an increased sensitivity of p53nullCD45.1 T cells to IL-6 induced STAT3 phosphorylation. Administration of a STAT3 inhibitor to p53nullCD45.1 mice reduced the frequency of Th17 cells and alleviated autoimmune pathology. This is the first report, to our knowledge, revealing the contribution of T-cell p53 in the suppression of autoimmunity by controlling Th17 differentiation. This study suggests that p53 serves as a guardian of proper immunological functions and that the p53-STAT3-Th17 axis might be a therapeutic target for autoimmunity.
- Copyright © 2011 by The American Association of Immunologists, Inc.