Differential trafficking of ligands trogocytosed via CD28 versus CTLA4 promotes collective cellular control of co-stimulation

Simon Zenke, Mauricio P. Sica, Florian Steinberg, Julia Braun, Alicia Zink, Alina Gavrilov, Alexander Hilger, Aditya Arra, Monika Brunner-Weinzierl, Roland Elling, Niklas Beyersdorf, Tim Lämmermann, Cristian R. Smulski and Jan C. Rohr ()
Additional contact information
Simon Zenke: Albert-Ludwigs-University
Mauricio P. Sica: Centro Atómico Bariloche, Comisión Nacional de Energía Atómica (CNEA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
Florian Steinberg: Albert-Ludwigs-University Freiburg
Julia Braun: Albert-Ludwigs-University
Alicia Zink: Albert-Ludwigs-University
Alina Gavrilov: Max Planck Institute of Immunobiology and Epigenetics
Alexander Hilger: Albert-Ludwigs-University
Aditya Arra: Otto-von-Guericke-University
Monika Brunner-Weinzierl: Otto-von-Guericke-University
Roland Elling: Albert-Ludwigs-University
Niklas Beyersdorf: University of Würzburg
Tim Lämmermann: Max Planck Institute of Immunobiology and Epigenetics
Cristian R. Smulski: Centro Atómico Bariloche, Comisión Nacional de Energía Atómica (CNEA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
Jan C. Rohr: Albert-Ludwigs-University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Intercellular communication is crucial for collective regulation of cellular behaviors. While clustering T cells have been shown to mutually control the production of key communication signals, it is unclear whether they also jointly regulate their availability and degradation. Here we use newly developed reporter systems, bioinformatic analyses, protein structure modeling and genetic perturbations to assess this. We find that T cells utilize trogocytosis by competing antagonistic receptors to differentially control the abundance of immunoregulatory ligands. Specifically, ligands trogocytosed via CD28 are shuttled to the T cell surface, enabling them to co-stimulate neighboring T cells. In contrast, CTLA4-mediated trogocytosis targets ligands for degradation. Mechanistically, this fate separation is controlled by different acid-sensitivities of receptor-ligand interactions and by the receptor intracellular domains. The ability of CD28 and CTLA4 to confer different fates to trogocytosed ligands reveals an additional layer of collective regulation of cellular behaviors and promotes the robustness of population dynamics.

Date: 2022
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DOI: 10.1038/s41467-022-34156-1

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