title: miR-29ab1 deficiency identifies a negative feedback loop controlling Th1 bias that is dysregulated in multiple sclerosis.
abstract: Th cell programming and function is tightly regulated by complex biological networks to prevent excessive inflammatory responses and autoimmune disease. The importance of microRNAs (miRNAs) in this process is highlighted by the preferential Th1 polarization of Dicer-deficient T cells that lack miRNAs. Using genetic knockouts, we demonstrate that loss of endogenous miR-29, derived from the miR-29ab1 genomic cluster, results in unrestrained T-bet expression and IFN-γ production. miR-29b regulates T-bet and IFN-γ via a direct interaction with the 3' untranslated regions, and IFN-γ itself enhances miR-29b expression, establishing a novel regulatory feedback loop. miR-29b is increased in memory CD4(+) T cells from multiple sclerosis (MS) patients, which may reflect chronic Th1 inflammation. However, miR-29b levels decrease significantly upon T cell activation in MS patients, suggesting that this feedback loop is dysregulated in MS patients and may contribute to chronic inflammation. miR-29 thus serves as a novel regulator of Th1 differentiation, adding to the understanding of T cell-intrinsic regulatory mechanisms that maintain a balance between protective immunity and autoimmunity.
authors: Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA.
authors: Kristen M
authors: KM
authors: Smith
authors: Mireia
authors: M
authors: Guerau-de-Arellano
authors: Stefan
authors: S
authors: Costinean
authors: Jessica L
authors: JL
authors: Williams
authors: Arianna
authors: A
authors: Bottoni
authors: Gina
authors: G
authors: Mavrikis Cox
authors: Abhay R
authors: AR
authors: Satoskar
authors: Carlo M
authors: CM
authors: Croce
authors: Michael K
authors: MK
authors: Racke
authors: Amy E
authors: AE
authors: Lovett-Racke
authors: Caroline C
authors: CC
authors: Whitacre
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D047369:Chromatin Immunoprecipitation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D025461:Feedback, Physiological; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*
chemical_list: C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs