PRDM1 encodes B lymphocyte-induced maturation protein 1 (BLIMP1), also known as a master regulator of T-cell homeostasis. We observed a negative relationship between Blimp-1 and IL-21 based on our previous data that Blimp-1 overexpression in T cells suppresses autoimmune diabetes while Blimp-1 deficient T cells contribute to colitis in NOD mice. Reanalysis of published datasets also reveals an inverse correlation between PRDM1 and IL21 in Crohn's disease. Here, we illustrate that Blimp-1 represses IL-21 by reducing chromatin accessibility and evicting an IL-21 activator c-Maf from the Il21 promoter. Moreover, IL-21-accelerated autoimmune diabetogenesis in small ubiquitin-like modifier-defective c-Maf transgenic mice can be overridden by Blimp-1 overexpression-mediated reduction in permissive chromatin structures at Il21 promoter. An autoregulatory feedback loop to harness IL-21 expression is unveiled by the evidence that addition of IL-21 induces time-dependent Blimp-1 expression and subsequently enriches its binding to the Il21 promoter to suppress IL-21 overproduction. Furthermore, intervention of this feedback loop by IL-21 blockade, IL-21R.Fc administration or IL-21 receptor deletion, attenuates Blimp-1 deficiency-mediated colitis and reinforces the circuit between Blimp-1 and IL-21 in the regulation of autoimmunity. We highlight the translation of Blimp-1-based epigenetic and transcriptomic profiles applicable to a personalized medicine approach in autoimmune diseases.
