CBP/P300 Inhibition Impairs CD4+ T Cell Activation: Implications for Autoimmune Disorders

Autor: Lucas Wilhelmus Picavet, Anoushka A. K. Samat, Jorg Calis, Lotte Nijhuis, Rianne Scholman, Michal Mokry, David F. Tough, Rabinder K. Prinjha, Sebastiaan J. Vastert, Jorg van Loosdregt
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Biomedicines, Vol 12, Iss 6, p 1344 (2024)
Druh dokumentu: article
ISSN: 12061344
2227-9059
DOI: 10.3390/biomedicines12061344
Popis: T cell activation is critical for an effective immune response against pathogens. However, dysregulation contributes to the pathogenesis of autoimmune diseases, including Juvenile Idiopathic Arthritis (JIA). The molecular mechanisms underlying T cell activation are still incompletely understood. T cell activation promotes the acetylation of histone 3 at Lysine 27 (H3K27ac) at enhancer and promoter regions of proinflammatory cytokines, thereby increasing the expression of these genes which is essential for T cell function. Co-activators E1A binding protein P300 (P300) and CREB binding protein (CBP), collectively known as P300/CBP, are essential to facilitate H3K27 acetylation. Presently, the role of P300/CBP in human CD4+ T cells activation remains incompletely understood. To assess the function of P300/CBP in T cell activation and autoimmune disease, we utilized iCBP112, a selective inhibitor of P300/CBP, in T cells obtained from healthy controls and JIA patients. Treatment with iCBP112 suppressed T cell activation and cytokine signaling pathways, leading to reduced expression of many proinflammatory cytokines, including IL-2, IFN-γ, IL-4, and IL-17A. Moreover, P300/CBP inhibition in T cells derived from the inflamed synovium of JIA patients resulted in decreased expression of similar pathways and preferentially suppressed the expression of disease-associated genes. This study underscores the regulatory role of P300/CBP in regulating gene expression during T cell activation while offering potential insights into the pathogenesis of autoimmune diseases. Our findings indicate that P300/CBP inhibition could potentially be leveraged for the treatment of autoimmune diseases such as JIA in the future.
Databáze: Directory of Open Access Journals
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