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

Abstract

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.

SHP-1-mediated inhibitory signals promote responsiveness and anti-tumour functions of natural killer cells

“…Unlike other immune cells, such as B cells 30 , CD4 þ T cells 41 , regulatory T cells 42 , dendritic cells and neutrophils 43 , we show here that SHP-1-deficient NK cells are hyporesponsive and do not promote inflammation or autoimmunity. NK cells are, to our knowledge, the only cell type in which a lack of SHP-1 increases, rather than decreases, the activation threshold.…”

The tyrosine phosphatase SHP-1 dampens murine Th17 development

“…Genotyping for all mice was performed as previously described. 23 C57BL/6 and rag1 Ϫ/Ϫ (C57BL/6) were obtained from The Jackson Laboratory. CD4-Cre (C57BL/6) mice were obtained from Taconic Farms.…”

“…We first asked whether SHP-1 affected intestinal Th17 development in vivo using the motheaten DO11.10 mouse model. 23 have been demonstrated to contribute to colitis, we examined the intestines for pathologic signs of disease or damage. However, basally, the intestines of me/ϩ and me/me mice showed no signs of intestinal damage or inflammation despite having higher percentages of Th17 cells ( Figure 1B).…”

“…SHP-1-deficient mice have increased percentages of Th17 cells in their Peyer patches and intestinal lamina propria, and T cells with decreased SHP-1 activity hyper-respond to IL-6 or IL-21 stimulation, in turn generating higher numbers of Th17 cells. As an independent nongenetic approach, we used sodium stibogluconate (SSG), a small molecule inhibitor of SHP-1 activity 23,24 that is currently tested in clinical trials as treatment option of patients with advanced solid tumors. [25][26][27] SSG-mediated inhibition of SHP-1 again demonstrated the regulatory role of SHP-1 in Th17 differentiation.…”

“…SSG used at 10 g/mL has been determined to inhibit 99% of SHP-1 activity with no detectable effect on other phosphatases. 23,24 EC 50 determination for IL-6 and IL-21 dose-responses. To determine the EC 50 of IL-6 and IL-21 for optimal TH17 differentiation, the maximal percentage of differentiated Th17 cells per experiment was set to 100%, and all other percentages were calculated in relation to this highest Th17 population.…”