Though not required for normal development (Pannu et al. 2015), USP21 is essential in innate and adaptive immune responses (Tao et al. 2014). It deubiquitinates the Th2 specific transcription factor GATA3. This positive regulation is important for the function of regulatory T cells (Zhang et al. 2013). USP21 also deubiquitinates IL-33, which is both a cytokine and a chromatin-associated nuclear protein known as Nuclear factor from high endothelial venule (NF-HEV), which is associated with many inflammatory diseases (Garlanda et al. 2013). IL-33 can bind to the RELA (NFkB p65) promoter region, inducing endothelial cell activation (Choi et al. 2012). Depletion of USP21 reduces IL-33 protein levels and IL-33-mediated RELA promoter activity (Tao et al. 2014).