The Transcription Factor T-Bet Is Regulated by MicroRNA-155 in Murine Anti-Viral CD8+ T Cells via SHIP-1.

Yvonne M. Mueller,Christopher J. Stairiker,Alison J. Carey,Erietta Stelekati,Inge Brouwers-Haspels,Joseph A. Fraietta,Peter D. Katsikis,Adam J. Fike,Laurine C. Rijsbergen,Marjan van Meurs,Panagiota I. Spantidea,E. John Wherry,Donald T. Gracias,Jennifer L. Hope,Rosemarieke C. Klop,Stefan J. Erkeland

doi:10.3389/fimmu.2017.01696

Yvonne M. Mueller, Christopher J. Stairiker + Show 14 more

Open Access

https://doi.org/10.3389/fimmu.2017.01696

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Abstract

We report here that the expression of the transcription factor T-bet, which is known to be required for effector cytotoxic CD8+ T lymphocytes (CTL) generation and effector memory cell formation, is regulated in CTL by microRNA-155 (miR-155). Importantly, we show that the proliferative effect of miR-155 on CD8+ T cells is mediated by T-bet. T-bet levels in CTL 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, and SHIP-1 directly downregulated T-bet. Our studies reveal an important and unexpected signaling axis between miR-155, T-bet, and SHIP-1 in in vivo CTL responses and suggest an important signaling module that regulates effector CTL immunity.

Highlights

Cytotoxic CD8+ T cells (CTLs) are an essential component of the adaptive immune system, responsible for the clearance or control of cells infected with viruses or intracellular bacteria and tumors [1, 2]
Increased expansion of miR-155-OE OT-I CD8+ T cells was observed in the spleen (1.8 ± 0.3 × 106 versus 5.3 ± 1.4 × 106, scrambled ctrl OT-I versus miR-155 OE OT-I, respectively, p = 0.023) and the mediastinal lymph nodes (MLNs) (0.2 ± 0.4 × 105 versus 0.8 ± 0.3 × 105, scrambled ctrl OT-I versus miR-155 OE OT-I, respectively, p = 0.029) 10 days post-infection (Figures 1C,D)
Since miR-155 is upregulated in effector CD8+ T lymphocytes (CTL) and we have previously shown that the absence of miR-155 significantly reduces effective CTL responses to infection [16], we argued that its forced overexpression would enhance the CTL response

Summary

Introduction

Cytotoxic CD8+ T cells (CTLs) are an essential component of the adaptive immune system, responsible for the clearance or control of cells infected with viruses or intracellular bacteria and tumors [1, 2]. Identifying the mechanisms that control the formation of effector and memory CTL is essential for rational vaccine design and immunotherapeutic approaches. Transcription factors have been recognized as crucial elements that control and direct the fate of CTL toward effector or memory differentiation states [3, 4]. The transcription factors T-bet, Eomes, Blimp-1, and Bcl-6 have been shown to regulate the differentiation and function of CTL [5]. T-bet- and Eomes-deficient mice have shown that the “graded expression” of these transcription factors regulate the early effector and memory phenotype of CTL in response to infection with lymphocytic choriomeningitis virus (LCMV) [3]. Understanding how T-bet expression is regulated in CTL is critical for our understanding of the pathways that control effector and memory CTL formation

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