Targeting mTORC2 for lupus treatment
People with lupus and mouse models of lupus have abnormally high levels of mTORC2 — a signaling molecule that stimulates immune activity by promoting antibody production and destabilizing the regulatory controls that normally keep the immune system in check. Dr, Zeng discovered that when mTORC2 is eliminated from the mouse models, their immune systems calm down and their lupus symptoms improve. The Lupus Innovation Award will allow Dr. Zeng to now figure out how mTORC2 contributes to lupus as well as to search for a molecule that can inhibit its activity in animal models and people to provide a more targeted treatment that might avoid the broad immunosuppressive effects of the current therapies.
What this study means for people with lupus
Dr. Zeng has found a metabolic signaling molecule called mTORC2 that is present at elevated levels in mouse models of lupus; perhaps a molecule that blocks it could point to a promising treatment.
Prior literatures have demonstrated that mTOR signaling, composed of mTORC1 and mTORC2 pathways, is elevated in lupus patients and mouse models of lupus. One of the key pathogenic cellular alterations associated with lupus severity is the increased differentiation of follicular helper T cells (Tfh), which drives high affinity antibody production by B cells. Our previous studies have demonstrated that both mTORC1 and mTORC2 critically contribute to Tfh differentiation. Furthermore, studies from our group and others have shown that mTORC1 is essential for naive T cell quiescence exit and differentiation of all effector T cell lineages, but mTORC2 preferentially promotes Tfh differentiation with minor contribution to other effector T cell lineages. Finally, elevated mTORC2 leads to regulatory T cell (Treg) instability, which eventually causes lupus-like autoimmunity in mouse models. Thus, we hypothesize that targeting mTORC2 can ameliorate lupus specifically through inhibition of Tfh and promotion of Tregs, without immune suppression accompanied by mTORC1 inhibition. Our preliminary data show that genetic ablation of mTORC2 in T cells significantly reverses the systemic immune activation in a mouse model of lupus. The specific aims of this proposal are, (1) To evaluate mTORC2 activity in infiltrating T cells in kidney biopsies from lupus nephritis patients; (2) To provide proof-of-principle evidence that pharmacological targeting mTORC2 benefit lupus in mouse model and to define the underlying mechanisms. The long-term objectives are to establish mTORC2 as a novel target for therapeutic treatment of lupus.