title: Cytoskeletal adaptivity regulates T cell receptor signaling.
abstract: The factors that govern T cell activation control the initiation and progression of adaptive immune responses. T cells recognize their cognate antigen on the surface of antigen-presenting cells (APCs) through the T cell receptor, which results in the formation of a contact region (immune synapse) between the two cells and the activation of the T cells. Activated T cells proliferate and differentiate into effector T cells that secrete cytokines, provide help to B cells, and kill target cells. We asked whether the actin cytoskeleton governs differences in signaling in effector T cells versus naïve (unstimulated) T cells. Using atomic force microscopy and quantitative confocal microscopy, we found that naïve T cells had a mechanically stiffer cortical cytoskeleton than that of effector cells, which resulted in naïve cells forming smaller immune synapses with APCs. This suggests that the cytoskeletal stiffness of the T cell before it undergoes antigen stimulation predicts its subsequent dynamic engagement with APCs and its activation potential. Cytoskeletal rigidity depended on the activity of the actin-severing enzyme cofilin through a pathway requiring the small guanosine triphosphatase RhoA and the kinases ROCK (Rho-activated kinase) and LIMK. These findings suggest that the baseline cytoskeletal state controls T cell responses and that the underlying pathway could be a therapeutic target for modulating adaptive immunity.
authors.affiliation: Stanford Immunology, Stanford University, Stanford, CA 94305, USA.|Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Timothy J
authors.identifier: http://orcid.org/0000-0002-9882-0001
authors.initials: TJ
authors.lastname: Thauland
authors.affiliation: Stanford Biophysics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Kenneth H
authors.identifier: http://orcid.org/0000-0002-0294-0202
authors.initials: KH
authors.lastname: Hu
authors.affiliation: Stanford Immunology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Marc A
authors.identifier: http://orcid.org/0000-0003-3328-7231
authors.initials: MA
authors.lastname: Bruce
authors.affiliation: Stanford Immunology, Stanford University, Stanford, CA 94305, USA. mbutte@mednet.ucla.edu.|Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.|Stanford Biophysics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Manish J
authors.identifier: http://orcid.org/0000-0002-4490-5595
authors.initials: MJ
authors.lastname: Butte
mesh_terms: D008841:Actin Cytoskeleton / Q000276:immunology* / Q000378:metabolism; D056704:Adaptive Immunity / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D054461:Lim Kinases / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018625:Microscopy, Atomic Force; D018613:Microscopy, Confocal; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D054460:rho-Associated Kinases / Q000276:immunology / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000276:immunology / Q000378:metabolism
chemical_list: D011948:Receptors, Antigen, T-Cell; D054461:Lim Kinases; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein