Multiomics Analysis Identifies SOCS1 as Restraining T Cell Activation and Preventing Graft-Versus-Host Disease.
Adv Sci (Weinh)
; 9(21): e2200978, 2022 07.
Article
em En
| MEDLINE
| ID: mdl-35585676
ABSTRACT
Graft-versus-host disease (GVHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Inflammatory signaling pathways promote T-cell activation and are involved in the pathogenesis of GVHD. Suppressor of cytokine signaling 1 (SOCS1) is a critical negative regulator for several inflammatory cytokines. However, its regulatory role in T-cell activation and GVHD has not been elucidated. Multiomics analysis of the transcriptome and chromatin structure of granulocyte-colony-stimulating-factor (G-CSF)-administered hyporesponsive T cells from healthy donors reveal that G-CSF upregulates SOCS1 by reorganizing the chromatin structure around the SOCS1 locus. Parallel in vitro and in vivo analyses demonstrate that SOCS1 is critical for restraining T cell activation. Loss of Socs1 in T cells exacerbates GVHD pathogenesis and diminishes the protective role of G-CSF in GVHD mouse models. Further analysis shows that SOCS1 inhibits T cell activation not only by inhibiting the colony-stimulating-factor 3 receptor (CSF3R)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway, but also by restraining activation of the inflammasome signaling pathway. Moreover, high expression of SOCS1 in T cells from patients correlates with low acute GVHD occurrence after HSCT. Overall, these findings identify that SOCS1 is critical for inhibiting T cell activation and represents a potential target for the attenuation of GVHD.
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1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article