The overall objective of our research program is to understand the molecular mechanisms of leukocyte activation and migration during autoimmune diseases such as multiple sclerosis (MS). A large number of membrane receptors can initiate leukocyte activation and/or migration, which include antigen receptors, chemokine receptors, and integrins. While these receptors bind to a diverse array of extracellular ligands (first messengers), a common intracellular second messenger generated by them is PIP3 (phosphatidylinositol 3,4,5-trisphosphate); PIP3 in turn directs leukocyte activation and migration by binding to dozens of effector proteins (such as protein kinases AKT, BTK, and PDK1) that regulate gene expression and/or cytoskeleton remodeling. This application is inspired by our recent discovery that the genesis and function of the common lipid second messenger PIP3 are controlled by its professional transfer proteins of the TNFAIP8 (tumor necrosis factor-?-induced protein 8) family. The TNFAIP8 family possesses a specific hydrophobic cavity that is constitutively occupied by the acyl chains of phosphoinositides such as PIP3, and it is the only known transfer protein family of PIP3. We initially cloned the TIPE2 (TNFAIP8-like 2) gene from spinal cord of mice with experimental autoimmune encephalomyelitis (EAE) and found that it was preferentially expressed by leukocytes. We then generated TIPE2-deficient mice and found that they were significantly resistant to EAE. Unexpectedly, TIPE2-deficient myelin-specific TH1 and TH17 cells were hyper-sensitive to myelin antigens but had an intrinsic defect in migration into CNS. We therefore hypothesize that TNFAIP8 family confers the encephalitogenicity of myelin-specific T cells by controlling the genesis and function of common lipid second messengers that mediate both activation and migration. In its absence, the activation-induced surge of lipid second messengers destroys the internal PIP3 compass that guides cell migration, leading to the generation of hyper-active non-encephalitogenic TH1 and TH17 cells not capable of directional migration. This theory will be tested in both murine and human systems (including MS) using genetic, immunological, and biochemical approaches. Specifically, we will determine (I) the mechanism through which TIPE2 and TNFAIP8 regulate myelin-specific T cell activation, and (II) the mechanism through which TIPE2 and TNFAIP8 regulate leukocyte migration during autoimmune encephalomyelitis.
This study will help advance our understanding of the molecular mechanisms of leukocyte activation and migration and aid in identifying new molecular targets for treating inflammatory diseases such as multiple sclerosis. Therefore this proposal may advance both basic knowledge and clinical practice.
|Fayngerts, Svetlana A; Wang, Zhaojun; Zamani, Ali et al. (2017) Direction of leukocyte polarization and migration by the phosphoinositide-transfer protein TIPE2. Nat Immunol 18:1353-1360|
|Wang, Ting; Shi, Weiyun; Fan, Tingting et al. (2016) c-Rel is Required for the Induction of pTregs in the Eye but Not in the Gut Mucosa. Immunol Invest 45:776-786|