Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction.
Nature
; 567(7749): 525-529, 2019 03.
Article
en En
| MEDLINE
| ID: mdl-30814730
ABSTRACT
T cells become dysfunctional when they encounter self antigens or are exposed to chronic infection or to the tumour microenvironment1. The function of T cells is tightly regulated by a combinational co-stimulatory signal, and dominance of negative co-stimulation results in T cell dysfunction2. However, the molecular mechanisms that underlie this dysfunction remain unclear. Here, using an in vitro T cell tolerance induction system in mice, we characterize genome-wide epigenetic and gene expression features in tolerant T cells, and show that they are distinct from effector and regulatory T cells. Notably, the transcription factor NR4A1 is stably expressed at high levels in tolerant T cells. Overexpression of NR4A1 inhibits effector T cell differentiation, whereas deletion of NR4A1 overcomes T cell tolerance and exaggerates effector function, as well as enhancing immunity against tumour and chronic virus. Mechanistically, NR4A1 is preferentially recruited to binding sites of the transcription factor AP-1, where it represses effector-gene expression by inhibiting AP-1 function. NR4A1 binding also promotes acetylation of histone 3 at lysine 27 (H3K27ac), leading to activation of tolerance-related genes. This study thus identifies NR4A1 as a key general regulator in the induction of T cell dysfunction, and a potential target for tumour immunotherapy.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Linfocitos T
/
Regulación de la Expresión Génica
/
Genoma
/
Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Nature
Año:
2019
Tipo del documento:
Article
País de afiliación:
China