Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, United States; Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, United States; Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, United States; Department of Machine Learning, Carnegie Mellon University, Pittsburgh, United States; Freiburg Institute for Advanced Studies, Albert Ludwig University of Freiburg, Freiburg, Germany; Faculty of Biology, Albert Ludwig University of Freiburg, Freiburg, Germany
School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United States
Supramolecular signaling assemblies are of interest for their unique signaling properties. A µm scale signaling assembly, the central supramolecular signaling cluster (cSMAC), forms at the center of the interface of T cells activated by antigen-presenting cells. We have determined that it is composed of multiple complexes of a supramolecular volume of up to 0.5 µm3 and associated with extensive membrane undulations. To determine cSMAC function, we have systematically manipulated the localization of three adaptor proteins, LAT, SLP-76, and Grb2. cSMAC localization varied between the adaptors and was diminished upon blockade of the costimulatory receptor CD28 and deficiency of the signal amplifying kinase Itk. Reconstitution of cSMAC localization restored IL-2 secretion which is a key T cell effector function as dependent on reconstitution dynamics. Our data suggest that the cSMAC enhances early signaling by facilitating signaling interactions and attenuates signaling thereafter through sequestration of a more limited set of signaling intermediates.
