Impact of the Multiple Sclerosis-Associated Genetic Variant CD226 Gly307Ser on Human CD8 T-Cell Functions.
Neurol Neuroimmunol Neuroinflamm
; 11(6): e200306, 2024 Nov.
Article
em En
| MEDLINE
| ID: mdl-39231385
ABSTRACT
BACKGROUND AND OBJECTIVES:
The rs763361 nonsynonymous variant in the CD226 gene, which results in a glycine-to-serine substitution at position 307 of the CD226 protein, has been implicated as a risk factor of various immune-mediated diseases, including multiple sclerosis (MS). Compelling evidence suggests that this allele may play a significant role in predisposing individuals to MS by decreasing the immune-regulatory capacity of Treg cells and increasing the proinflammatory potential of effector CD4 T cells. However, the impact of this CD226 gene variant on CD8 T-cell functions, a population that also plays a key role in MS, remains to be determined.METHODS:
To study whether the CD226 risk variant affects human CD8 T-cell functions, we used CD8 T cells isolated from peripheral blood mononuclear cell of 16 age-matched healthy donors homozygous for either the protective or the risk allele of CD226. We characterized these CD8 T cells on T-cell receptor (TCR) stimulation using high-parametric flow cytometry and bulk RNAseq and through characterization of canonical signaling pathways and cytokine production.RESULTS:
On TCR engagement, the phenotype of ex vivo CD8 T cells bearing the protective (CD226-307Gly) or the risk (CD226-307Ser) allele of CD226 was largely overlapping. However, the transcriptomic signature of CD8 T cells from the donors carrying the risk allele presented an enrichment in TCR, JAK/STAT, and IFNγ signaling. We next found that the CD226-307Ser risk allele leads to a selective increase in the phosphorylation of the mitogen-activated protein kinases extracellular signal-regulated kinases 1 and 2 (ERK1/2) associated with enhanced phosphorylation of STAT4 and increased production of IFNγ.DISCUSSION:
Our data suggest that the CD226-307Ser risk variant imposes immune dysregulation by increasing the pathways related to IFNγ signaling in CD8 T cells, thereby contributing to the risk of developing chronic inflammation.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Antígenos de Diferenciação de Linfócitos T
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Linfócitos T CD8-Positivos
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Esclerose Múltipla
Limite:
Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Neurol Neuroimmunol Neuroinflamm
Ano de publicação:
2024
Tipo de documento:
Article