Inhibiting Wipf2 downregulation by transgenic expression of its 3′ mRNA‐untranslated region improves cytotoxicity and vaccination response

Lymphocyte activation results in profound changes in the abundance of mRNA transcripts many of which are downregulated. The Wiskott–Aldrich syndrome (WAS) protein (WASP) family is critical for productive T‐cell receptor signaling and actin reorganization. The WASP signal pathway includes the WAS/WAS‐like (WASL) interacting protein family 2 (WIPF2) gene also known as WIRE/WICH. We show that both human WIPF2 and mouse Wipf2 are mice, alternatively spliced within the 3′ untranslated region (3′UTR) resulting in two major transcripts of approximately 4.5 and 6 kb in size. Following T‐cell activation, the level of human WIPF2 and mouse Wipf2 mRNA rapidly declines. In mice, this decline is accompanied by a marked reduction in WIPF2 protein levels. Transgenic expression of a 240‐bp fragment derived from a highly conserved terminal 3′UTR found within the 6‐kb transcript blocks Wipf2 downregulation. These effects may be mediated by competitive inhibition of microinhibitory RNA (miRNA) regulation since the 6‐kb‐derived transgene and the 4.5‐kb transcript share functional binding sites for miRNA146a. Blocking Wipf2 gene and protein repression resulted in improved T‐cell responses to antigen immunization in vivo as well as in vitro cytotoxic T‐cell killing. Collectively, these data suggest that early downregulation of this immunologically relevant gene controls the intensity of selective lymphocyte functions.