ABHD11 inhibition drives sterol metabolism to modulate T cell effector function 2 and alleviate autoimmunity

Jenkins, Benjamin, Jenkins, Yasmin, Ponce-Garcia, Fernando, Moscrop, Chloe, Perry, Iain, Hitchings, Matthew, Uribe, Alejandro, Bernuzzi, Federico, Eastham, Simon, Cronin, James, Berisha, Ardena, Howell, Alexandra, Davies, Joanne, Blagih, Julianna, Veale, Douglas, Davies, Luke, Niphakis, Micah, Finlay, David, Sinclair, Linda, Cravatt, Benjamin, Hogan, Andrew, Nathan, James, Fearon, Ursula, Sumpton, David, Vande Voorde, Johan, Dias do Vale, Goncalo, McDonald, Jeffrey, Jones, Gareth, Pearson, James ORCID: https://orcid.org/0000-0002-2867-2269, Vincent, Emma and Jones, Nicholas ORCID: https://orcid.org/0000-0002-7098-6114 2025. ABHD11 inhibition drives sterol metabolism to modulate T cell effector function 2 and alleviate autoimmunity. [Online]. bioRxiv: openRxiv. Available at: https://doi.org/10.1101/2025.03.19.643996

PDF - Submitted Pre-Print Version Download (26MB)

Abstract

Chronic inflammation in autoimmunity is driven by T cell hyperactivation. This unregulated response to self is fuelled by heightened metabolic programmes, which offers a promising new direction to uncover novel treatment strategies. α/β-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase that maintains the catalytic function of α-ketoglutarate dehydrogenase (α-KGDH), and its expression in CD4+ T cells has been linked to remission status in rheumatoid arthritis (RA). However, the importance of ABHD11 in regulating T cell metabolism and function – and thus, the downstream implication for autoimmunity – is yet to be explored. Here, we show that pharmacological inhibition of ABHD11 dampens cytokine production by human and mouse T cells. Mechanistically, the anti-inflammatory effects of ABHD11 inhibition are attributed to increased 24,25-epoxycholesterol (24,25-EC) biosynthesis and subsequent liver X receptor (LXR) activation, which arise from a compromised TCA cycle. The impaired cytokine profile established by ABHD11 inhibition is extended to two patient cohorts of autoimmunity. Importantly, using a murine model of accelerated type 1 diabetes (T1D), we show that targeting ABHD11 suppresses cytokine production in antigen-specific T cells and delays the onset of diabetes in vivo. Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T cell-mediated autoimmunity.

Item Type:	Website Content
Date Type:	Published Online
Status:	Submitted
Schools:	Schools > Medicine
Publisher:	openRxiv
Date of Acceptance:	19 March 2025
Last Modified:	03 Jun 2025 13:31
URI:	https://orca.cardiff.ac.uk/id/eprint/178226

Actions (repository staff only)

Edit Item