TY - JOUR
T1 - T cell receptor and IL-2 signaling strength control memory CD8+ T cell functional fitness via chromatin remodeling
AU - Chin, Shu Shien
AU - Guillen, Erik
AU - Chorro, Laurent
AU - Achar, Sooraj
AU - Ng, Karina
AU - Oberle, Susanne
AU - Alfei, Francesca
AU - Zehn, Dietmar
AU - Altan-Bonnet, Grégoire
AU - Delahaye, Fabien
AU - Lauvau, Grégoire
N1 - Funding Information:
The authors thank the Einstein FACS and genomic core facilities, and John Wherry (U Penn) for sharing his ATAC-seq protocol. This work was funded by the National Institute of Health Grants (NIH) AI103338, Hirschl Caulier Award to G.L. L.C. received fellowships from ARC, Fondation Bettencourt-Schuller and the American Association of Immunology (AAI). S.S.C. and E.G. were respectively supported by NIH training grant T32 AI070117 and NIH MSTP training grant T32 GM7288. Core resources for FACS were supported by the Einstein Cancer Center (NCI cancer center support grant 2P30CA013330).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85128893516&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85128893516&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-29718-2
DO - 10.1038/s41467-022-29718-2
M3 - Article
C2 - 35474218
AN - SCOPUS:85128893516
VL - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2240
ER -