title: Oxidation of cofilin mediates T cell hyporesponsiveness under oxidative stress conditions.
abstract: Oxidative stress leads to impaired T cell activation. A central integrator of T cell activation is the actin-remodelling protein cofilin. Cofilin is activated through dephosphorylation at Ser3. Activated cofilin enables actin dynamics through severing and depolymerization of F-actin. Binding of cofilin to actin is required for formation of the immune synapse and T cell activation. Here, we showed that oxidatively stressed human T cells were impaired in chemotaxis- and costimulation-induced F-actin modulation. Although cofilin was dephosphorylated, steady-state F-actin levels increased under oxidative stress conditions. Mass spectrometry revealed that cofilin itself was a target for oxidation. Cofilin oxidation induced formation of an intramolecular disulfide bridge and loss of its Ser3 phosphorylation. Importantly, dephosphorylated oxidized cofilin, although still able to bind to F-actin, did not mediate F-actin depolymerization. Impairing actin dynamics through oxidation of cofilin provides a molecular explanation for the T cell hyporesponsiveness caused by oxidative stress.
authors.affiliation: Institute for Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Klemke
authors.forename: Guido H
authors.initials: GH
authors.lastname: Wabnitz
authors.forename: Faustina
authors.initials: F
authors.lastname: Funke
authors.forename: Beate
authors.initials: B
authors.lastname: Funk
authors.forename: Henning
authors.initials: H
authors.lastname: Kirchgessner
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Samstag
mesh_terms: D051339:Actin Depolymerizing Factors / Q000737:chemistry / Q000378:metabolism*; D000199:Actins / Q000378:metabolism*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002634:Chemotaxis, Leukocyte; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D054461:Lim Kinases / Q000378:metabolism; D008213:Lymphocyte Activation; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D018106:CD28 Antigens; D017252:CD3 Complex; D006861:Hydrogen Peroxide; D054461:Lim Kinases