title: The actin-driven spatiotemporal organization of T-cell signaling at the system scale.
abstract: T cells are activated through interaction with antigen-presenting cells (APCs). During activation, receptors and signaling intermediates accumulate in diverse spatiotemporal distributions. These distributions control the probability of signaling interactions and thus govern information flow through the signaling system. Spatiotemporally resolved system-scale investigation of signaling can extract the regulatory information thus encoded, allowing unique insight into the control of T-cell function. Substantial technical challenges exist, and these are briefly discussed herein. While much of the work assessing T-cell spatiotemporal organization uses planar APC substitutes, we focus here on B-cell APCs with often stark differences. Spatiotemporal signaling distributions are driven by cell biologically distinct structures, a large protein assembly at the interface center, a large invagination, the actin-supported interface periphery as extended by smaller individual lamella, and a newly discovered whole-interface actin-driven lamellum. The more than 60 elements of T-cell activation studied to date are dynamically distributed between these structures, generating a complex organization of the signaling system. Signal initiation and core signaling prefer the interface center, while signal amplification is localized in the transient lamellum. Actin dynamics control signaling distributions through regulation of the underlying structures and drive a highly undulating T-cell/APC interface that imposes substantial constraints on T-cell organization. We suggest that the regulation of actin dynamics, by controlling signaling distributions and membrane topology, is an important rheostat of T-cell signaling.
authors.affiliation: Department of Immunology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Kole T
authors.initials: KT
authors.lastname: Roybal
authors.forename: Parisa
authors.initials: P
authors.lastname: Sinai
authors.forename: Paul
authors.initials: P
authors.lastname: Verkade
authors.forename: Robert F
authors.initials: RF
authors.lastname: Murphy
authors.forename: Christoph
authors.initials: C
authors.lastname: Wülfing
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication; D006801:Humans; D008213:Lymphocyte Activation; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000199:Actins
keywords: T-cell signaling; actin; imaging; systems biology