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[Seminar Notification]: Je-Min Choi, Ph.D.(11.26.2020)
2020-11-23

[Seminar Notification]: Je-Min Choi, Ph.D.(11.26.2020)

1. Title: In vivo induction of regulatory T cells by CTLA-4 signaling peptide ameliorates neuroinflammation in autoimmune encephalomyelitis
2. Speaker: Je-Min Choi, Ph.D.
3. Affiliation: Department of Life Science, College of Natural Sciences,
Hanyang University, Seoul, Republic of Korea
4. Date: 2020. 11. 26. (Thu) 16:00
5. Place: Online Seminar(Zoom)
6. Abstract: Multiple sclerosis (MS) is a neuroinflammatory disease in central nervous system (CNS) mainly caused by T and B cells results in demyelination lead to axonal injury. Th1 and Th17 cells are sought to be important target to suppress while currently lymphocyte trafficking or B cell depletion is popular strategy. Regulatory T (Treg) cells play a key role in immune tolerance to self-antigen and prevents autoimmune disease. However, none of immune modulatory drugs have been approved for human trial yet based on in vivo Treg generation. Here, we demonstrate signaling function of cytoplasmic domain of CTLA-4 (ctCTLA-4) in T cells regarding Treg differentiation. We dissected each signaling motifs in ctCTLA-4 to generate immune modulatory peptide which does not require its ligand interaction. To introduce exogenous peptide into the cells, we previously identified a superior cell-penetrable peptide which is even BBB-penetrating peptide, dNP2 and now we generated chimeric peptides combined to ctCTLA-4 to evaluate its role in Treg induction in vivo. We found that this cell-penetrating form of truncated CTLA-4 peptide (dNP2-ctCTLA-4) could be able to induce Foxp3 expression during the differentiation of naïve CD4 T cells into Th0, Th1, Th2, and Th17 cells that is dependent on TGF-β. In particular, lysine residue in ctCTLA-4 is critical for Foxp3 expression presumably related to molecular interaction with PKC-η to interfere phosphorylation of smad2/3 under TGF-β signaling. Moreover, dNP2-ctCTLA-4 treatment in vivo shows remarkable therapeutic effects in EAE model which is an animal model of multiple sclerosis. In vivo increase of Treg cells by dNP2-ctCTLA-4 treatment assures prolonged suppression of disease relapse while CTLA-4Ig could not. Furthermore, this chimeric CTLA-4 signaling peptide could induce human Tregs in vitro and in vivo as well as in MS patient PBMCs. These results collectively suggest that BBB-permeable cytoplasmic domain of CTLA-4 peptide would be a novel agent to make successful induction of regulatory T cells in vivo to control CNS autoimmune diseases like MS.