title: Coronin 1A is an essential regulator of the TGFβ receptor/SMAD3 signaling pathway in Th17 CD4(+) T cells.
abstract: Transforming growth factor β (TGFβ) plays a central role in maintaining immune homeostasis by regulating the initiation and termination of immune responses and thus preventing the development of autoimmune diseases. In this study, we describe an essential mechanism by which the actin regulatory protein Coronin 1A (Coro1A) ensures the proper response of Th17 CD4(+) T cells to TGFβ. Coro1A has been established as a key player in T cell survival, migration, activation, and Ca(2+) regulation in naive T cells. We show that mice lacking Coro1a developed less severe experimental autoimmune encephalomyelitis (EAE). Unexpectedly, upon the re-induction of EAE, Coro1a(-/-) mice exhibited enhanced EAE signs that correlated with increased numbers of IL-17 producing CD4(+) cells in the central nervous system (CNS) compared to wild-type mice. In vitro differentiated Coro1a(-/-) Th17 CD4(+) T cells consistently produced more IL-17 than wild-type cells and displayed a Th17/Th1-like phenotype in regard to the expression of the Th1 markers T-bet and IFNγ. Mechanistically, the Coro1a(-/-) Th17 cell phenotype correlated with a severe defect in TGFβR-mediated SMAD3 activation. Taken together, these data provide experimental evidence of a non-redundant role of Coro1A in the regulation of Th17 CD4(+) cell effector functions and, subsequently, in the development of autoimmunity.
authors.affiliation: Experimental Cell Genetics, Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Austria.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kaminski
authors.forename: Natascha
authors.initials: N
authors.lastname: Hermann-Kleiter
authors.forename: Marlies
authors.initials: M
authors.lastname: Meisel
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Thuille
authors.forename: Shane
authors.initials: S
authors.lastname: Cronin
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hara
authors.forename: Friedrich
authors.initials: F
authors.lastname: Fresser
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Gottfried
authors.initials: G
authors.lastname: Baier
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051900:Smad3 Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; D008840:Microfilament Proteins; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; C072061:coronin proteins; D007371:Interferon-gamma