title: Dendritic cell motility and T cell activation requires regulation of Rho-cofilin signaling by the Rho-GTPase activating protein myosin IXb.
abstract: Directed migration of stimulated dendritic cells (DCs) to secondary lymphoid organs and their interaction with Ag-specific T cells is a prerequisite for the induction of primary immune responses. In this article, we show that murine DCs that lack myosin IXB (Myo9b), a motorized negative regulator of RhoA signaling, exhibit increased Rho signaling activity and downstream acto-myosin contractility, and inactivation of the Rho target protein cofilin, an actin-depolymerizing factor. On a functional level, Myo9b(-/-) DCs showed impaired directed migratory activity both in vitro and in vivo. Moreover, despite unaltered Ag presentation and costimulatory capabilities, Myo9b(-/-) DCs were poor T cell stimulators in vitro in a three-dimensional collagen matrix and in vivo, associated with altered DC-T cell contact dynamics and T cell polarization. Accordingly, Myo9b(-/-) mice showed an attenuated ear-swelling response in a model of contact hypersensitivity. The impaired migratory and T cell stimulatory capacity of Myo9b(-/-) DCs was restored in large part by pharmacological activation of cofilin. Taken together, these results identify Myo9b as a negative key regulator of the Rho/RhoA effector Rho-kinase [Rho-associated coiled-coil-forming kinase (ROCK)]/LIM domain kinase signaling pathway in DCs, which controls cofilin inactivation and myosin II activation and, therefore may control, in part, the induction of adaptive immune responses.
authors.affiliation: Institute of Molecular Cell Biology, Westfalian Wilhelms University-Münster, Münster 48149, Germany.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Stefanie
authors.initials: S
authors.lastname: Pektor
authors.forename: Sandra
authors.initials: S
authors.lastname: Balkow
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Hemkemeyer
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Liu
authors.forename: Kay
authors.initials: K
authors.lastname: Grobe
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hanley
authors.forename: Limei
authors.initials: L
authors.lastname: Shen
authors.forename: Matthias
authors.initials: M
authors.lastname: Bros
authors.forename: Talkea
authors.initials: T
authors.lastname: Schmidt
authors.forename: Martin
authors.initials: M
authors.lastname: Bähler
authors.forename: Stephan
authors.initials: S
authors.lastname: Grabbe
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation; D002465:Cell Movement / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D003877:Dermatitis, Contact / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009218:Myosins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D051339:Actin Depolymerizing Factors; D020690:GTPase-Activating Proteins; C113469:myosin IXB; C085379:rho GTPase-activating protein; D054460:rho-Associated Kinases; D009218:Myosins