The immunoproteasome (iPr), a unique form of the proteasome found in cells of the immune system, regulates cytokine production and differentiation of Th1 and Th17 cells in vitro in an NF-kB independent manner. However, the role of the iPr in other T-cell subsets and the specific molecular signaling events regulated by the iPr are not well understood. We found that FoxP3 and TGF-β expression increased in Treg cells exposed to a selective iPr inhibitor (ONX 0914, formerly PR-957) but that IL-4 production in Th2 cells was unaffected by iPr inhibition. Interestingly, increased FoxP3 expression was noted in Th0 and Th1 cells exposed to ONX 0914. Inhibition of the iPr resulted in reduced phosphorylation of STAT1 and STAT3 in Th1 and Th17 cells, respectively. Decreased basal and IL-6 stimulated STAT3 phosphorylation was noted immediately following iPr inhibition suggesting a receptor proximal event but at later timepoints coincided with reduced gene expression. After a brief exposure to ONX 0914, Th17 and Treg cells show a similar pattern of protein accumulation as measured by 2D Diffference Gel Electrophoresis and included the regulatory subunit of PP2A, a protein phosphatase known to regulate STAT3 and other transcription factors. Collectively, these results suggest that the iPr regulates Th cell plasticity via PP2A activity.
- Copyright © 2011 by The American Association of Immunologists, Inc.