T cell receptor and IL-2 signaling strength control memory CD8+ T cell functional fitness via chromatin remodeling

Shu Shien Chin, Erik Guillen, Laurent Chorro, Sooraj Achar, Karina Ng, Susanne Oberle, Francesca Alfei, Dietmar Zehn, Grégoire Altan-Bonnet, Fabien Delahaye () and Grégoire Lauvau ()
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Shu Shien Chin: Albert Einstein College of Medicine, Department of Microbiology and Immunology
Erik Guillen: Albert Einstein College of Medicine, Department of Microbiology and Immunology
Laurent Chorro: Albert Einstein College of Medicine, Department of Microbiology and Immunology
Sooraj Achar: Center for Cancer Research, ImmunoDynamics Group
Karina Ng: Albert Einstein College of Medicine, Department of Microbiology and Immunology
Susanne Oberle: Technical University of Munich
Francesca Alfei: Technical University of Munich
Dietmar Zehn: Technical University of Munich
Grégoire Altan-Bonnet: Center for Cancer Research, ImmunoDynamics Group
Fabien Delahaye: Albert Einstein College of Medicine, Department of Genetics
Grégoire Lauvau: Albert Einstein College of Medicine, Department of Microbiology and Immunology

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract Cognate antigen signal controls CD8+ T cell priming, expansion size and effector versus memory cell fates, but it is not known if and how it modulates the functional features of memory CD8+ T cells. Here we show that the strength of T cell receptor (TCR) signaling controls the requirement for interleukin-2 (IL-2) signals to form a pool of memory CD8+ T cells that competitively re-expand upon secondary antigen encounter. Combining strong TCR and intact IL-2 signaling during priming synergistically induces genome-wide chromatin accessibility in regions targeting a wide breadth of biological processes, consistent with greater T cell functional fitness. Chromatin accessibility in promoters of genes encoding for stem cell, cell cycle and calcium-related proteins correlates with faster intracellular calcium accumulation, initiation of cell cycle and more robust expansion. High-dimensional flow-cytometry analysis of these T cells also highlights higher diversity of T cell subsets and phenotypes with T cells primed with stronger TCR and IL-2 stimulation than those primed with weaker strengths of TCR and/or IL-2 signals. These results formally show that epitope selection in vaccine design impacts memory CD8+ T cell epigenetic programming and function.

Date: 2022
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DOI: 10.1038/s41467-022-29718-2

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