Transient protein accumulation at the center of the T cell antigen-presenting cell interface drives efficient IL-2 secretion

Danielle J Clark, Laura E McMillan, Sin Lih Tan, Gaia Bellomo, Clementine Massoue, Harry Thompson, Lidiya Mykhaylechko, Dominic Alibhai, Xiongtao Ruan, Kentner L Singleton, Minna Du, Alan Hedges, Pamela L Schwartzberg, Paul Verkade, Robert F Murphy, Christoph Wuellfing

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Abstract

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.
Original languageEnglish
Number of pages29
JournaleLife
Volume8
DOIs
Publication statusPublished - 30 Oct 2019

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    Clark, D. J., McMillan, L. E., Tan, S. L., Bellomo, G., Massoue, C., Thompson, H., Mykhaylechko, L., Alibhai, D., Ruan, X., Singleton, K. L., Du, M., Hedges, A., Schwartzberg, P. L., Verkade, P., Murphy, R. F., & Wuellfing, C. (2019). Transient protein accumulation at the center of the T cell antigen-presenting cell interface drives efficient IL-2 secretion. eLife, 8. https://doi.org/10.7554/eLife.45789