Rapid in vitro generation of bona fide exhausted CD8+ T cells is accompanied by Tcf7 promotor methylation

Autoři: Manzhi Zhao aff001;  Caoimhe H. Kiernan aff001;  Christopher J. Stairiker aff001;  Jennifer L. Hope aff002;  Leticia G. Leon aff001;  Marjan van Meurs aff001;  Inge Brouwers-Haspels aff001;  Ruben Boers aff003;  Joachim Boers aff003;  Joost Gribnau aff003;  Wilfred F. J. van IJcken aff005;  Eric M. Bindels aff006;  Remco M. Hoogenboezem aff006;  Stefan J. Erkeland aff001;  Yvonne M. Mueller aff001;  Peter D. Katsikis aff001
Působiště autorů: Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands aff001;  Cancer Immunology and Tumor Microenvironment Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States of America aff002;  Department of Developmental Biology, Erasmus University Medical Center, Rotterdam, the Netherlands aff003;  Oncode Institute, Erasmus University Medical Center, Rotterdam, The Netherlands aff004;  Center for Biomics, Erasmus University Medical Center, Rotterdam, the Netherlands aff005;  Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands aff006
Vyšlo v časopise: Rapid in vitro generation of bona fide exhausted CD8+ T cells is accompanied by Tcf7 promotor methylation. PLoS Pathog 16(6): e1008555. doi:10.1371/journal.ppat.1008555
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008555


Exhaustion is a dysfunctional state of cytotoxic CD8+ T cells (CTL) observed in chronic infection and cancer. Current in vivo models of CTL exhaustion using chronic viral infections or cancer yield very few exhausted CTL, limiting the analysis that can be done on these cells. Establishing an in vitro system that rapidly induces CTL exhaustion would therefore greatly facilitate the study of this phenotype, identify the truly exhaustion-associated changes and allow the testing of novel approaches to reverse or prevent exhaustion. Here we show that repeat stimulation of purified TCR transgenic OT-I CTL with their specific peptide induces all the functional (reduced cytokine production and polyfunctionality, decreased in vivo expansion capacity) and phenotypic (increased inhibitory receptors expression and transcription factor changes) characteristics of exhaustion. Importantly, in vitro exhausted cells shared the transcriptomic characteristics of the gold standard of exhaustion, CTL from LCMV cl13 infections. Gene expression of both in vitro and in vivo exhausted CTL was distinct from T cell anergy. Using this system, we show that Tcf7 promoter DNA methylation contributes to TCF1 downregulation in exhausted CTL. Thus this novel in vitro system can be used to identify genes and signaling pathways involved in exhaustion and will facilitate the screening of reagents that prevent/reverse CTL exhaustion.

Klíčová slova:

Anergy – Cytokines – Cytotoxic T cells – DNA methylation – Gene expression – T cell receptors – T cells – Transcription factors


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