Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function

Area of Science:

• Immunology
• Metabolic pathways
• Drug discovery

Background:

• Alpha/beta-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase crucial for alpha-ketoglutarate dehydrogenase (α-KGDH) function.
• ABHD11 expression in CD4+ T-cells correlates with rheumatoid arthritis (RA) remission, but its role in T-cell metabolism and function remains unclear.

Purpose of the Study:

• To investigate the role of ABHD11 in regulating T-cell metabolism and function.
• To explore ABHD11 as a potential therapeutic target for T-cell-mediated inflammatory and autoimmune diseases.

Main Methods:

• Pharmacological inhibition of ABHD11 in human and mouse T-cells.
• Analysis of cytokine production, 24,25-epoxycholesterol (24,25-EC) biosynthesis, and liver X receptor (LXR) activation.
• Assessment of T-cell profiles in patient cohorts with autoimmune diseases.
• Evaluation of ABHD11 inhibition in murine models of accelerated type 1 diabetes (T1D).

Main Results:

• ABHD11 inhibition reduced cytokine production in T-cells.
• Inhibition led to increased 24,25-EC biosynthesis and LXR activation due to TCA cycle compromise.
• The observed anti-inflammatory effects were consistent across patient cohorts and in T1D mouse models.
• Targeting ABHD11 suppressed antigen-specific T-cell cytokine production and delayed diabetes onset in female mice.

Conclusions:

• ABHD11 plays a significant role in regulating T-cell inflammatory responses.
• ABHD11 inhibition offers a promising therapeutic strategy for T-cell-mediated inflammation and autoimmune conditions like T1D.
• Preclinical evidence supports ABHD11 as a viable drug target for treating autoimmune diseases.