SHP-1 Regulates Conventional T Cell Resistance to Suppression by Regulatory T Cells

Background: Conventional T (Tcon) cells are crucial in shaping the immune response, whether it is protection against a pathogen, attack of tumor cells, or prevention of autoimmunity. In each of these settings, regulatory T (Treg) cells can suppress the activation, proliferation, or function of Tcons. It has become clear that in many autoimmune diseases, Tregs are functional yet fail to prevent the Tcon response against self. In contrast, tumors are enriched for Tregs, creating a suppressive microenvironment that inhibits anti-tumor Tcon responses. Thus, the balance between Treg suppression and Tcon activation can propagate disease if not finely tuned. This study aims to understand the molecular mechanism that governs Tcon susceptibility to Treg suppression. We have identified the phosphatase SHP-1 as a regulator of Tcon resistance to Treg suppression. Methods: To study the role of SHP-1 in Tcon resistance to Treg suppression, we used a mouse model in which SHP-1 is deleted specifically in T cells. Tcons were isolated from mice and their in vitro proliferation in response to T cell receptor (TCR) stimulation in the presence or absence of Tregs was measured. In complementary assays, wt mice were injected with an SHP-1 inhibitor, sodium stibogluconate (SSG), and in vitro proliferation of Tcons in the presence of Tregs was measured. Finally, Akt activation was measured in TCR/CD28-stimulated SHP-1^-/- and wt Tcons. Results: We found that a greater percentage of SHP-1^-/- Tcons responded to TCR stimulation and resisted in vitro Treg suppression compared to wt Tcons. Moreover, Tcons from mice treated with SSG acquired resistance to Treg-mediated suppression. To address the mechanism by which SHP-1 deficiency allows Tcons to resist Treg-mediated suppression, we examined the PI3K/Akt pathway, a potential target of SHP-1 regulation. Preliminary results indicate that SHP-1^-/- Tcons have enhanced Akt activation in response to TCR stimulation. Conclusions: Our data indicate that SHP-1 negatively regulates the responsiveness of T cells to TCR-mediated stimulation and modulates susceptibility to Treg-mediated suppression. Consistent with studies suggesting that hyperactivation of Akt may confer resistance to Treg suppression, we found enhanced Akt activation in SHP-1^-/- Tcons, indicating Akt is a downstream target of SHP-1. We will next investigate whether SHP-1 regulates resistance of effector T cells to Treg suppression in vivo. Long-term, we plan to target SHP-1 or Akt for immunotherapeutic Tcon modulation, which may be translatable to autoimmune or cancer settings.