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

  • bioRxiv. 2025 Mar 19:2025.03.19.643996. doi: 10.1101/2025.03.19.643996.
Benjamin J Jenkins  1 ,  Yasmin R Jenkins  1 ,  Fernando M Ponce-Garcia  1 ,  Chloe Moscrop  2 ,  Iain A Perry  1 ,  Matthew D Hitchings  1 ,  Alejandro H Uribe  3 ,  Federico Bernuzzi  3 ,  Simon Eastham  2 ,  James G Cronin  1 ,  Ardena Berisha  4 ,  Alexandra Howell  5 ,  Joanne Davies  5 ,  Julianna Blagih  6  7 ,  Douglas J Veale  8 ,  Luke C Davies  1 ,  Micah Niphakis  9 ,  David K Finlay  10 ,  Linda V Sinclair  11 ,  Benjamin F Cravatt  9 ,  Andrew E Hogan  4 ,  James A Nathan  12 ,  Ursula Fearon  13 ,  David Sumpton  3 ,  Johan Vande Voorde  3  14 ,  Goncalo Dias do Vale  15 ,  Jeffrey G McDonald  15 ,  Gareth W Jones  2 ,  James A Pearson  5 ,  Emma E Vincent  16  17 ,  Nicholas Jones  1
Affiliations
  • 1. Institute of Life Science, Swansea University Medical School, Swansea University, SA2 8PP, UK.
  • 2. Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, Bristol, BS8 1TD, UK.
  • 3. Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.
  • 4. Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland.
  • 5. Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, CF14 4XN, UK.
  • 6. The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
  • 7. University of Montreal, Maisonneuve-Rosemont Hospital Research Centre, Montreal, 5414 Assomption Blvd, H1T 2M4, Canada.
  • 8. EULAR Centre of Excellence, Centre for Arthritis and Rheumatic Diseases, St Vincent's University Hospital, Dublin, Ireland.
  • 9. Department of Chemistry, Scripps Research, La Jolla, California 92037, United States.
  • 10. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearce Street, Dublin, Ireland.
  • 11. Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
  • 12. Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Department of Medicine, University of Cambridge, Cambridge, CB2 0AW, UK.
  • 13. Molecular Rheumatology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearce Street, Dublin, Ireland.
  • 14. School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, G61 1QH, UK.
  • 15. Center for Human Nutrition, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.
  • 16. School of Translational Health Sciences, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK.
  • 17. Integrative Epidemiology Unit, School of Population Health Science, University of Bristol, Bristol, BS8 2BN, UK.
PMID: 40166327 DOI: 10.1101/2025.03.19.643996
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.

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