The transcription factor T-bet is regulated by microRNA-155 in murine anti-viral CD8+ T cells via SHIP-1.

Abstract

Abstract MicroRNAs (miRNAs) are small, single-stranded non-coding RNAs that play essential roles in regulating key cellular processes, and are highly conserved across species. However, the regulatory role of microRNAs in generating effective CD8+ T cell (CTL) responses to viral infection and tumors is only now being elucidated. Microarray miRNA expression profiling identified unique expression patterns of miRNAs in naïve and effector anti-viral CTL. In particular, microRNA-155 was significantly upregulated in effector CTL. Previously, we have demonstrated that miR-155 is essential to CD8+ T cell responses to viral and intracellular bacterial infections. In the present study, we show that miR-155 overexpression in CTL augments anti-viral effector CTL and skews memory CD8+ T cells towards an effector memory phenotype. MiR-155 overexpression resulted in enhanced T-bet expression, which is known to be required for effector CTL and to promote effector memory cell formation. Importantly, we show that the proliferative effect of miR-155 on CD8+ T cells is mediated by T-bet. In CTL, T-bet levels were controlled in vivo by miR-155 via SH2 (Src homology 2)-containing inositol phosphatase-1 (SHIP-1), a known direct target of miR-155. Our studies have revealed an important and unexpected link between miR-155, T-bet transcription factor and SHIP-1 in the context of CTL responses to an in vivo viral infection.