MS CD49d + CD154 + Lymphocytes Reprogram Oligodendrocytes into Immune Reactive Cells Affecting CNS Regeneration

• Published in: Cells (Basel, Switzerland) Vol. 8; no. 12; p. 1508
• Main Authors: Piatek, Paweł, Namiecinska, Magdalena, Domowicz, Małgorzata, Przygodzka, Patrycja, Wieczorek, Marek, Michlewska, Sylwia, Lewkowicz, Natalia, Tarkowski, Maciej, Lewkowicz, Przemysław
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 25.11.2019; MDPI
• Subjects: CD40L protein; CD49d antigen; Chemokines; Cloning; Cytokines; Experimental allergic encephalomyelitis; Glial stem cells; Glycoproteins; Immunological memory; Inflammation; Lymphocytes; Lymphocytes B; Memory cells; miRNA; Multiple sclerosis; Myelin; Myelin basic protein; Myelin proteolipid protein; Myelination; Oligodendrocytes; Peptides; Proteins; Proteolipid protein; Regeneration; United States > US; Germany; oligodendrocyte precursor cells; myelin-specific lymphocytes; multiple sclerosis; remyelination
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells8121508

The critical aspect in multiple sclerosis (MS) progression involves insufficient regeneration of CNS resulting from deficient myelin synthesis by newly generated oligodendrocytes (OLs). Although many studies have focused on the role of autoreactive lymphocytes in the inflammatory-induced axonal loss, the problem of insufficient remyelination and disease progression is still unsolved. To determine the effect of myelin-specific lymphocytes on OL function in MS patients and in a mouse model of MS, we cultured myelin induced MS CD49d CD154 circulating lymphocytes as well as Experimental Autoimmune Encephalomyelitis (EAE) mouse brain-derived T and memory B cells with maturing oligodendrocyte precursor cells (OPCs). We found that myelin-specific CD49d CD154 lymphocytes affected OPC maturation toward formation of immune reactive OLs. Newly generated OLs were characterized by imbalanced myelin basic protein (MBP) and proteolipid protein (PLP) production as well as proinflammatory chemokine/cytokine synthesis. The analysis of cellular pathways responsible for OL reprogramming revealed that CD49d CD154 lymphocytes affected miRNA synthesis by dysregulation of polymerase II activity. miR-665 and ELL3 turned out to be the main targets of MS myelin-specific lymphocytes. Neutralization of high intracellular miR-665 concentration restored miRNA and MBP/PLP synthesis. Together, these data point to new targets for therapeutic intervention promoting CNS remyelination.