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

Lucas Wilhelmus Picavet¹, Anoushka A K Samat¹, Jorg Calis¹

¹Center for Translational Immunology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.

|June 27, 2024

Summary

This summary is machine-generated.

Inhibiting P300/CBP in T cells reduces pro-inflammatory cytokine production, offering a potential treatment strategy for autoimmune diseases like Juvenile Idiopathic Arthritis (JIA). This highlights P300/CBP

Keywords:

H3K27ac JIA P300/CBP T cell activation autoimmune diseases cytokines iCBP112

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Area of Science:

Immunology
Molecular Biology
Autoimmune Diseases

Background:

T cell activation is crucial for immunity but its dysregulation drives autoimmune diseases like Juvenile Idiopathic Arthritis (JIA).
Histone 3 Lysine 27 acetylation (H3K27ac) at cytokine gene promoters/enhancers is vital for T cell activation.
P300/CBP co-activators are essential for H3K27ac, but their role in human T cell activation and JIA is unclear.

Purpose of the Study:

To investigate the role of P300/CBP in human CD4+ T cell activation.
To evaluate the therapeutic potential of P300/CBP inhibition in autoimmune conditions, specifically JIA.

Main Methods:

Utilized iCBP112, a selective P300/CBP inhibitor, on T cells from healthy donors and JIA patients.
Analyzed the effects of P300/CBP inhibition on T cell activation markers and cytokine gene expression.
Examined T cells from the inflamed synovium of JIA patients.

Main Results:

iCBP112 treatment suppressed T cell activation and key cytokine signaling pathways (IL-2, IFN-γ, IL-4, IL-17A).
P300/CBP inhibition reduced the expression of proinflammatory cytokines in T cells from both healthy and JIA individuals.
Inhibition preferentially suppressed disease-associated genes in T cells from JIA patients' synovium.

Conclusions:

P300/CBP plays a significant role in regulating gene expression during T cell activation.
P300/CBP inhibition demonstrates potential as a therapeutic strategy for autoimmune diseases like JIA.
Targeting P300/CBP may offer a novel approach to managing T cell-driven autoimmune pathogenesis.