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

Jenkins, B. J.; Jenkins, Y. R.; Ponce-Garcia, F. M.; Moscrop, C.; Perry, I. A.; Hitchings, M. D.; Uribe, A. H.; Bernuzzi, F.; Eastham, S.; Cronin, J. G.; Berisha, A.; Howell, A.; Davies, J.; Blagih, J.; Veale, D. J.; Davies, L. C.; Niphakis, M.; Finlay, D. K.; Sinclair, L. V.; Cravatt, B.; Hogan, A. E.; Nathan, J. A.; Fearon, U.; Sumpton, D.; Vande Voorde, J.; Dias do Vale, G.; McDonald, J. G.; Jones, G. W.; Pearson, J. A.; Vincent, E. E.; Jones, N.

doi:10.1101/2025.03.19.643996

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bioRxiv · 10.1101/2025.03.19.643996

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

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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. /{beta}-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase that maintains the catalytic function of -ketoglutarate dehydrogenase (-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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/643996v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@bb3fcborg.highwire.dtl.DTLVardef@1594fc8org.highwire.dtl.DTLVardef@84e078org.highwire.dtl.DTLVardef@1ad023e_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Jenkins, B. J., Jenkins, Y. R., Ponce-Garcia, F. M., Moscrop, C., Perry, I. A., Hitchings, M. D., Uribe, A. H., Bernuzzi, F., Eastham, S., Cronin, J. G., Berisha, A., Howell, A., Davies, J., Blagih, J., Veale, D. J., Davies, L. C., Niphakis, M., Finlay, D. K., Sinclair, L. V., Cravatt, B., Hogan, A. E., Nathan, J. A., Fearon, U., Sumpton, D., Vande Voorde, J., Dias do Vale, G., McDonald, J. G., Jones, G. W., Pearson, J. A., Vincent, E. E., Jones, N.. 2025-03-19. ABHD11 inhibition drives sterol metabolism to modulate T cell effector function and alleviate autoimmunity. https://doi.org/10.1101/2025.03.19.643996

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