Trans-presentation of IL-15 modulates STAT5 activation and Bcl-6 expression in TH1 cells.

Ian D. Cooley,Kenneth J. Oestreich,Kaitlin A. Read

doi:10.1038/srep15722

Abstract

During infection, naïve CD4+ T helper cells differentiate into specialized effector subsets based upon environmental signals propagated by the cytokine milieu. Recently, this paradigm has been complicated by the demonstration that alterations in the cytokine environment can result in varying degrees of plasticity between effector T helper cell populations. Therefore, elucidation of the mechanisms by which cytokines regulate T helper cell differentiation decisions is increasingly important. The gamma common cytokine IL-15 is currently undergoing clinical trials for the treatment of malignancies, due to its well-established role in the regulation of natural killer and CD8+ T cell immune responses. However, the effect of IL-15 signaling on CD4+ T cell activity is incompletely understood. One mechanism by which IL-15 activity is conferred is through trans-presentation via the IL-15 receptor alpha subunit. Here, we demonstrate that differentiated TH1 cells are responsive to trans-presented IL-15. Importantly, while trans-presentation of IL-15 results in STAT5 activation and maintenance of the TH1 gene program, IL-15 treatment alone allows for increased Bcl-6 expression and the upregulation of a TFH-like profile. Collectively, these findings describe a novel role for IL-15 in the modulation of CD4+ T cell responses and provide valuable insight for the use of IL-15 in immunotherapeutic approaches.

Highlights

Respectively[19,22]
Previous work has demonstrated that signaling through the gamma common (γ c) cytokine IL-2 is indispensable for the promotion and maintenance of the T helper 1 (TH1) cell fate while, the withdrawal of IL-2 results in a loss of TH1 cell identity and the up-regulation of a T follicular helper (TFH)-like gene expression profile[36,40]
To begin to test this hypothesis, we examined whether IL-15 treatment alone would be sufficient to both promote TH1 gene expression patterns and repress the induction of the TFH gene program following IL-2 withdrawal from differentiated TH1 cells

Summary

Introduction

Respectively[19,22]. Like IL-2, IL-15 signals through intracellular domains of the γ c and IL-2Rβ subunits, which employ the janus kinase 1 (Jak1) and Jak[3] kinases to phosphorylate and activate the transcription factor STAT519,22. Exposure of TH1 cells to IL-15 in the absence IL-15Rα resulted in decreased STAT5 activation and increased expression of the TFH lineage defining transcription factor Bcl-6. Elevated Bcl-6 expression levels correlated with a decrease in Blimp-1 expression and the upregulation of a TFH-like gene program including Cxcr[5], Il6ra, Tnfsf[8], and Sh2d1a. These results describe previously unappreciated effects of IL-15 signaling on the differential expression of TH1 and TFH gene profiles, and provide added insight into the functional properties of this immunotherapeutic cytokine

Methods

Results

Conclusion