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In Vivo Induction of Regulatory T Cells Via CTLA-4 Signaling Peptide to Control Autoimmune Encephalomyelitis and Prevent Disease Relapseopen access

Authors
Kim, Gil-RanKim, Won-JuLim, SanghoLee, Hong-GyunKoo, Ja-HyunNam, Kyung-HoKim, Sung-MinPark, Sung-DongChoi, Je-Min
Issue Date
Jul-2021
Publisher
WILEY
Keywords
autoimmunity; CTLA& #8208; 4; EAE (experimental autoimmune encephalomyelitis); multiple sclerosis; regulatory T cells
Citation
ADVANCED SCIENCE, v.8, no.14, pp.1 - 17
Indexed
SCIE
SCOPUS
Journal Title
ADVANCED SCIENCE
Volume
8
Number
14
Start Page
1
End Page
17
URI
https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/996
DOI
10.1002/advs.202004973
ISSN
2198-3844
Abstract
Regulatory T cells play a key role in immune tolerance to self-antigens, thereby preventing autoimmune diseases. However, no drugs targeting Treg cells have been approved for clinical trials yet. Here, a chimeric peptide is generated by conjugation of the cytoplasmic domain of CTLA-4 (ctCTLA-4) with dNP2 for intracellular delivery, dNP2-ctCTLA-4, and evaluated Foxp3 expression during Th0, Th1, Treg, and Th17 differentiation dependent on TGF-beta. The lysine motif of ctCTLA-4, not tyrosine motif, is required for Foxp3 expression for Treg induction and amelioration of experimental autoimmune encephalomyelitis (EAE). Transcriptome analysis reveals that dNP2-ctCTLA-4-treated T cells express Treg transcriptomic patterns with properties of suppressive functions. In addition, the molecular interaction between the lysine motif of ctCTLA-4 and PKC-eta is critical for Foxp3 expression. Although both CTLA-4-Ig and dNP2-ctCTLA-4 treatment in vivo ameliorated EAE progression, only dNP2-ctCTLA-4 requires Treg cells for inhibition of disease progression and prevention of relapse. Furthermore, the CTLA-4 signaling peptide is able to induce human Tregs in vitro and in vivo as well as from peripheral blood mononuclear cells (PBMCs) of multiple sclerosis patients. These results collectively suggest that the chimeric CTLA-4 signaling peptide can be used for successful induction of regulatory T cells in vivo to control autoimmune diseases, such as multiple sclerosis.
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