title: L-plastin regulates the stability of the immune synapse of naive and effector T-cells.
abstract: T-cells need to be tightly regulated during their activation and effector phase to assure an appropriate defence against cancer or pathogens and - vice versa - to avoid autoimmune reactions. Regulatory signals are provided via the immune synapse between T-cells and antigen-presenting cells (APCs) or target cells. The stability and kinetics of immune synapse formation is critical for proper T-cell functions. It requires dynamic rearrangements of the actin cytoskeleton necessary for organized spatio-temporal redistribution of receptors and adhesion molecules. We identified glucocorticoid-sensitive phosphorylation of serine 5 on the actin-bundling protein L-plastin as one important signalling event for this regulation. Using imaging flow cytometry as well as confocal and super-resolution microscopy we showed that L-plastin relocalizes to the immune synapse upon antigen encounter, where it associates with the β2-subunit of LFA-1 (CD11a/CD18). Interfering with L-plastin expression or activation leads to a defective LFA-1 recruitment and unstable T-cell/APC contacts. Consequently, the lack of L-plastin diminishes T-cell activation, proliferation and proximal effector responses such as cytokine production. On the other hand, a pro-oxidative milieu leads to prolonged activation of L-plastin resulting in a stronger enrichment of LFA-1 in the cytolytic immune synapse. Concomitant stabilization of conjugates formed by cytotoxic T-cells (CTLs) and their target cells impairs the ability of CTLs to kill more than one target cells (serial killing), which de facto leads to a downregulation of T-cell cytotoxicity. Together, we demonstrate that activation and spacial distribution of L-plastin regulates the maturation and stability of activating and cytolytic immune synapses important for T-cell activation and effector functions.
authors.affiliation: Institute of Immunology, Section Molecular Immunology, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany. Electronic address: guido.wabnitz@immu.uni-heidelberg.de.
authors.forename: Guido
authors.initials: G
authors.lastname: Wabnitz
authors.affiliation: Institute of Immunology, Section Molecular Immunology, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany.
authors.forename: Emre
authors.initials: E
authors.lastname: Balta
authors.affiliation: Institute of Immunology, Section Molecular Immunology, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Samstag
mesh_terms: D008841:Actin Cytoskeleton / Q000737:chemistry / Q000276:immunology; D000818:Animals; D001665:Binding Sites; D003713:Dendritic Cells / Q000737:chemistry / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D054992:Immunological Synapses / Q000737:chemistry / Q000378:metabolism*; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000276:immunology*; D008840:Microfilament Proteins / Q000235:genetics / Q000276:immunology*; D010766:Phosphorylation; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000737:chemistry / Q000276:immunology*
chemical_list: C047262:LCP1 protein, human; D016169:Lymphocyte Function-Associated Antigen-1; D008840:Microfilament Proteins; D021122:Protein Subunits