MicroRNAs targeting TGF‐β signaling exacerbate central nervous system autoimmunity by disrupting regulatory T cell development and function

• Published in: European journal of immunology Vol. 54; no. 6; pp. e2350548 - n/a
• Main Authors: Rau, Christina N., Severin, Mary E., Lee, Priscilla W., Deffenbaugh, Joshua L., Liu, Yue, Murphy, Shawn P., Petersen‐Cherubini, Cora L., Lovett‐Racke, Amy E.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.06.2024
• Subjects: Animal models; Animals; Autoimmune diseases; Autoimmunity; Autoimmunity - immunology; CD4 antigen; Cell Differentiation - immunology; Central nervous system; Central Nervous System - immunology; Encephalomyelitis; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - immunology; Experimental allergic encephalomyelitis; Experimental autoimmune encephalomyelitis; Female; Helper cells; Homeostasis; Humans; Immunoregulation; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; MicroRNAs; MicroRNAs - genetics; MicroRNAs - immunology; miRNA; miRNAs; Multiple sclerosis; Multiple Sclerosis - genetics; Multiple Sclerosis - immunology; Neonates; Nervous system; Risk factors; Signal transduction; Signal Transduction - immunology; T cell receptors; T-Lymphocytes, Regulatory - immunology; TGF beta; Th1 Cells - immunology; Th17 Cells - immunology; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Tregs; Experimental autoimmune encephalomyelitis; Multiple sclerosis; miRNAs; TGF beta; Tregs
• ISSN: 0014-2980; 1521-4141; 1521-4141
• DOI: 10.1002/eji.202350548

Transforming growth factor beta (TGF‐β) signaling is essential for a balanced immune response by mediating the development and function of regulatory T cells (Tregs) and suppressing autoreactive T cells. Disruption of this balance can result in autoimmune diseases, including multiple sclerosis (MS). MicroRNAs (miRNAs) targeting TGF‐β signaling have been shown to be upregulated in naïve CD4 T cells in MS patients, resulting in a limited in vitro generation of human Tregs. Utilizing the murine model experimental autoimmune encephalomyelitis, we show that perinatal administration of miRNAs, which target the TGF‐β signaling pathway, enhanced susceptibility to central nervous system (CNS) autoimmunity. Neonatal mice administered with these miRNAs further exhibited reduced Treg frequencies with a loss in T cell receptor repertoire diversity following the induction of experimental autoimmune encephalomyelitis in adulthood. Exacerbated CNS autoimmunity as a result of miRNA overexpression in CD4 T cells was accompanied by enhanced Th1 and Th17 cell frequencies. These findings demonstrate that increased levels of TGF‐β‐associated miRNAs impede the development of a diverse Treg population, leading to enhanced effector cell activity, and contributing to an increased susceptibility to CNS autoimmunity. Thus, TGF‐β‐targeting miRNAs could be a risk factor for MS, and recovering optimal TGF‐β signaling may restore immune homeostasis in MS patients. Graphical : TGF‐β signaling targeting miRNAs that were differentially expressed in naive CD4 T cells of MS patients exacerbate CNS inflammation in experimental autoimmune encephalomyelitis (EAE). These miRNAs caused a reduction of nTregs in neonatal mice, a reduced TCR repertoire in Tregs in mice with EAE, and increased inflammatory CD4 T cells.