TY - JOUR
T1 - The order and logic of CD4 versus CD8 lineage choice and differentiation in mouse thymus
AU - Karimi, Mohammad M.
AU - Guo, Ya
AU - Cui, Xiaokai
AU - Pallikonda, Husayn A.
AU - Horková, Veronika
AU - Wang, Yi Fang
AU - Gil, Sara Ruiz
AU - Rodriguez-Esteban, Gustavo
AU - Robles-Rebollo, Irene
AU - Bruno, Ludovica
AU - Georgieva, Radina
AU - Patel, Bhavik
AU - Elliott, James
AU - Dore, Marian H.
AU - Dauphars, Danielle
AU - Krangel, Michael S.
AU - Lenhard, Boris
AU - Heyn, Holger
AU - Fisher, Amanda G.
AU - Štěpánek, Ondřej
AU - Merkenschlager, Matthias
N1 - Funding Information:
We thank Dr. B. Seddon (University College London) for discussion, Dr. J. Merkens-chlager (Rockefeller University) for critical reading of the manuscript, the referees for valuable suggestions, and Dr. G. Kassiotis (Crick Institute, London) for MHC class II−/− mice. Supported by the Medical Research Council, UK (B.L., A.G.F., M.M.), the Wellcome Trust (Investigator Award 099276/Z/12/Z to M.M.), the National Institutes of Health (NIH 1R35GM136284 to M.K.), and the Swiss National Science Foundation (SNSF Promys IZ11Z0_166538 to O.S.).
Publisher Copyright:
© 2021, The Author(s).
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/12
Y1 - 2021/12
N2 - CD4 and CD8 mark helper and cytotoxic T cell lineages, respectively, and serve as coreceptors for MHC-restricted TCR recognition. How coreceptor expression is matched with TCR specificity is central to understanding CD4/CD8 lineage choice, but visualising coreceptor gene activity in individual selection intermediates has been technically challenging. It therefore remains unclear whether the sequence of coreceptor gene expression in selection intermediates follows a stereotypic pattern, or is responsive to signaling. Here we use single cell RNA sequencing (scRNA-seq) to classify mouse thymocyte selection intermediates by coreceptor gene expression. In the unperturbed thymus, Cd4+Cd8a- selection intermediates appear before Cd4-Cd8a+ selection intermediates, but the timing of these subsets is flexible according to the strength of TCR signals. Our data show that selection intermediates discriminate MHC class prior to the loss of coreceptor expression and suggest a model where signal strength informs the timing of coreceptor gene activity and ultimately CD4/CD8 lineage choice.
AB - CD4 and CD8 mark helper and cytotoxic T cell lineages, respectively, and serve as coreceptors for MHC-restricted TCR recognition. How coreceptor expression is matched with TCR specificity is central to understanding CD4/CD8 lineage choice, but visualising coreceptor gene activity in individual selection intermediates has been technically challenging. It therefore remains unclear whether the sequence of coreceptor gene expression in selection intermediates follows a stereotypic pattern, or is responsive to signaling. Here we use single cell RNA sequencing (scRNA-seq) to classify mouse thymocyte selection intermediates by coreceptor gene expression. In the unperturbed thymus, Cd4+Cd8a- selection intermediates appear before Cd4-Cd8a+ selection intermediates, but the timing of these subsets is flexible according to the strength of TCR signals. Our data show that selection intermediates discriminate MHC class prior to the loss of coreceptor expression and suggest a model where signal strength informs the timing of coreceptor gene activity and ultimately CD4/CD8 lineage choice.
UR - http://www.scopus.com/inward/record.url?scp=85098670138&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-20306-w
DO - 10.1038/s41467-020-20306-w
M3 - Article
AN - SCOPUS:85098670138
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 99
ER -