Abstract
Central nervous system (CNS)-infiltrating effector T cells play critical roles in the development and progression of multiple sclerosis (MS). However, current drugs for MS are very limited due to the difficulty of delivering drugs into the CNS. Here we identify a cell-permeable peptide, dNP2, which efficiently delivers proteins into mouse and human T cells, as well as various tissues. Moreover, it enters the brain tissue and resident cells through blood vessels by penetrating the tightly organized blood–brain barrier. The dNP2-conjugated cytoplasmic domain of cytotoxic T-lymphocyte antigen 4 (dNP2-ctCTLA-4) negatively regulates activated T cells and shows inhibitory effects on experimental autoimmune encephalomyelitis in both preventive and therapeutic mouse models, resulting in the reduction of demyelination and CNS-infiltrating T helper 1 and T helper 17 cells. Thus, this study demonstrates that dNP2 is a blood–brain barrier-permeable peptide and dNP2-ctCTLA-4 could be an effective agent for treating CNS inflammatory diseases such as MS.
Highlights
Central nervous system (CNS)-infiltrating effector T cells play critical roles in the development and progression of multiple sclerosis (MS)
Multiple sclerosis is a human autoimmune disease caused by the induction of inflammation in the central nervous system (CNS) by myelin-specific T cells that cross the protective environment of the blood–brain barrier (BBB)[1]
We identified and optimized a human-derived CNSpermeable cell-permeable peptides (CPP) and applied it to an EAE model via conjugation with the cytoplasmic domain of cytotoxic T-lymphocyte antigen 4 to control autoimmune effector T-cell responses in the CNS
Summary
Central nervous system (CNS)-infiltrating effector T cells play critical roles in the development and progression of multiple sclerosis (MS). The use of high-intensity-focused ultrasound has been investigated to physically enhance drug delivery into the CNS for therapeutic purposes[10] Another strategy uses cationic cell-permeable peptides (CPP) via adsorptive-mediated transcytosis of barrier cells. In primary T cells, the liCTLA-4 protein inhibits T-cell activation by dephosphorylating the T-cell receptor (TcR) z-chain These studies revealed that the cytoplasmic tail of CTLA-4 could deliver negative signals without B7 binding to the extracellular ligand-binding domain. We previously reported that intracellular delivery of a recombinant CTLA-4 cytoplasmic domain (ctCTLA-4) efficiently inhibited phosphorylation of the TcR z-chain and mitogen-activated protein kinase, resulting in amelioration of allergic airway inflammation and autoimmune arthritis in experimental animal models[22,23]
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