Rapid in vitro generation of bona fide exhausted CD8+ T cells is accompanied by Tcf7 promotor methylation.
PLoS Pathog
; 16(6): e1008555, 2020 06.
Article
in En
| MEDLINE
| ID: mdl-32579593
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Promoter Regions, Genetic
/
CD8-Positive T-Lymphocytes
/
DNA Methylation
/
Hepatocyte Nuclear Factor 1-alpha
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Lymphocytic Choriomeningitis
/
Lymphocytic choriomeningitis virus
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
PLoS Pathog
Year:
2020
Type:
Article
Affiliation country:
Netherlands