The Protein Tyrosine Phosphatase SHP-1 Modulates the Suppressive Activity of Regulatory T Cells

Beirne B. Carter Center for Immunology Research, Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA.
The Journal of Immunology (Impact Factor: 4.92). 10/2010; 185(10):6115-27. DOI: 10.4049/jimmunol.1000622
Source: PubMed


The importance of regulatory T cells (Tregs) for immune tolerance is well recognized, yet the signaling molecules influencing their suppressive activity are relatively poorly understood. In this article, through in vivo studies and complementary ex vivo studies, we make several important observations. First, we identify the cytoplasmic tyrosine phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP-1) as an endogenous brake and modifier of the suppressive ability of Tregs; consistent with this notion, loss of SHP-1 expression strongly augments the ability of Tregs to suppress inflammation in a mouse model. Second, specific pharmacological inhibition of SHP-1 enzymatic activity via the cancer drug sodium stibogluconate potently augmented Treg suppressor activity both in vivo and ex vivo. Finally, through a quantitative imaging approach, we directly demonstrate that Tregs prevent the activation of conventional T cells and that SHP-1-deficient Tregs are more efficient suppressors. Collectively, our data reveal SHP-1 as a critical modifier of Treg function and a potential therapeutic target for augmenting Treg-mediated suppression in certain disease states.

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    • "Taken together, the data suggest that the mere presence of CTLA-4 is inhibitory to T cells, as was recently shown for PD-1 [59]. A similar inhibitory role has been proposed for Shp-1 [44,60], and a possible contribution of CTLA-4 to setting the activation threshold within T cells has been suggested for primed TCR-transgenic cells [61]. This intrinsic inhibitory mechanism may also contribute to the unresponsive nature of regulatory T cells, which constitutively express CTLA-4 [60,62]. "
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