Epigenetic control of p53 activity in regulatory T cells maintains their identity to prevent inflammation

Abstract

Abstract Regulatory T cells (Tregs) are critical guardians of immune homeostasis that must operate in diverse and often inflammatory conditions. However, the mechanisms that Tregs use to maintain their stability and function, especially in response to the stresses of distinct microenvironments, remain incompletely understood. Previous work identified the repressive chromatin modification histone 3 lysine 27 trimethylation (H3K27me3) as a rheostat for Treg function. Here, we find that loss of H3K27me3 in Tregs activates the tumor suppressor p53. Stabilization of p53 using the MDM2 inhibitor Nutlin-3 protected Tregs from losing their master transcription factor FOXP3 in vitro when cultured with the T helper 17 cytokines interleukin-6 and interleukin-1β, while p53 deficiency rendered Tregs more prone to FOXP3 loss. Treg-specific p53 deficiency resulted in the accumulation of cells that had lost Foxp3 expression (“ex-Tregs”) and a reduction of suppressive markers on Tregs specifically in the colon. Additionally, these mice exhibited inflammation in the colon at homeostasis and increased severity of induced colitis. These results demonstrate a specific role for p53 in the maintenance of Treg stability in inflammatory T helper 17–polarizing environments and present a possible target for improving Treg-based immunotherapies for diseases defined by intestinal inflammation, such as inflammatory bowel disease.