{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T07:45:00Z","timestamp":1775979900111,"version":"3.50.1"},"posted":{"date-parts":[[2025,3,19]]},"group-title":"Immunology","reference-count":65,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T00:00:00Z","timestamp":1742342400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  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. \u03b1\/\u03b2-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase that maintains the catalytic function of \u03b1-ketoglutarate dehydrogenase (\u03b1-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 \u2013 and thus, the downstream implication for autoimmunity \u2013 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\n                  <jats:italic>in vivo<\/jats:italic>\n                  . Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T cell-mediated autoimmunity.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"643996v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.03.19.643996","type":"posted-content","created":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T19:06:21Z","timestamp":1742583981000},"source":"Crossref","is-referenced-by-count":0,"title":["ABHD11 inhibition drives sterol metabolism to modulate T cell effector function and alleviate autoimmunity"],"prefix":"10.64898","author":[{"given":"Benjamin J.","family":"Jenkins","sequence":"first","affiliation":[{"name":"Institute of Life Science, Swansea University Medical School, Swansea University, SA2 8PP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasmin R.","family":"Jenkins","sequence":"additional","affiliation":[{"name":"Institute of Life Science, Swansea University Medical School, Swansea University, SA2 8PP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando M.","family":"Ponce-Garcia","sequence":"additional","affiliation":[{"name":"Institute of Life Science, Swansea University Medical School, Swansea University, SA2 8PP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chloe","family":"Moscrop","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, Bristol, BS8 1TD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iain A.","family":"Perry","sequence":"additional","affiliation":[{"name":"Institute of Life Science, Swansea University Medical School, Swansea University, SA2 8PP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew D.","family":"Hitchings","sequence":"additional","affiliation":[{"name":"Institute of Life Science, Swansea University Medical School, Swansea University, SA2 8PP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandro H.","family":"Uribe","sequence":"additional","affiliation":[{"name":"Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federico","family":"Bernuzzi","sequence":"additional","affiliation":[{"name":"Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Eastham","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, Bristol, BS8 1TD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James G.","family":"Cronin","sequence":"additional","affiliation":[{"name":"Institute of Life Science, Swansea University Medical School, Swansea University, SA2 8PP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ardena","family":"Berisha","sequence":"additional","affiliation":[{"name":"Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Howell","sequence":"additional","affiliation":[{"name":"Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, CF14 4XN, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanne","family":"Davies","sequence":"additional","affiliation":[{"name":"Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, CF14 4XN, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julianna","family":"Blagih","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK"},{"name":"University of Montreal, Maisonneuve-Rosemont Hospital Research Centre, Montreal, 5414 Assomption Blvd, H1T 2M4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas J.","family":"Veale","sequence":"additional","affiliation":[{"name":"EULAR Centre of Excellence, Centre for Arthritis and Rheumatic Diseases, St Vincent\u2019s University Hospital, Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luke C.","family":"Davies","sequence":"additional","affiliation":[{"name":"Institute of Life Science, Swansea University Medical School, Swansea University, SA2 8PP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Micah","family":"Niphakis","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Scripps Research, La Jolla, California 92037, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David K.","family":"Finlay","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearce Street, Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda V.","family":"Sinclair","sequence":"additional","affiliation":[{"name":"Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin F.","family":"Cravatt","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Scripps Research, La Jolla, California 92037, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5875-230X","authenticated-orcid":false,"given":"Andrew E.","family":"Hogan","sequence":"additional","affiliation":[{"name":"Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0248-1632","authenticated-orcid":false,"given":"James A.","family":"Nathan","sequence":"additional","affiliation":[{"name":"Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Department of Medicine, University of Cambridge, Cambridge, CB2 0AW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ursula","family":"Fearon","sequence":"additional","affiliation":[{"name":"Molecular Rheumatology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearce Street, Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Sumpton","sequence":"additional","affiliation":[{"name":"Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johan","family":"Vande Voorde","sequence":"additional","affiliation":[{"name":"Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK"},{"name":"School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, G61 1QH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Goncalo","family":"Dias do Vale","sequence":"additional","affiliation":[{"name":"Center for Human Nutrition, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey G.","family":"McDonald","sequence":"additional","affiliation":[{"name":"Center for Human Nutrition, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gareth W.","family":"Jones","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, Bristol, BS8 1TD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James A.","family":"Pearson","sequence":"additional","affiliation":[{"name":"Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, CF14 4XN, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma E.","family":"Vincent","sequence":"additional","affiliation":[{"name":"School of Translational Health Sciences, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK"},{"name":"Integrative Epidemiology Unit, School of Population Health Science, University of Bristol, Bristol, BS8 2BN, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4846-5117","authenticated-orcid":false,"given":"Nicholas","family":"Jones","sequence":"additional","affiliation":[{"name":"Institute of Life Science, Swansea University Medical School, Swansea University, SA2 8PP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041200001239000_2025.03.19.643996v1.1","doi-asserted-by":"crossref","unstructured":"Jones, N. et al. 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