Moscrop, C. | bioRxiv Science

bioRxiv2025

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

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

immunology↗

bioRxiv2022

Alternative paths to immune activation: the role of costimulatory risk genes for polygenic inflammatory disease in T helper cells

T cell activation pathways have been repeatedly implicated by genetic studies as being enriched for risk genes for immune and inflammatory diseases. Many of these risk genes code for costimulatory receptors or ligands. Costimulatory receptors are cell surface proteins on T cells, which are engaged by costimulatory ligands on antigen-presenting cells. Both costimulation and antigen binding are required to trigger T cell activation. In order to study the different pathways activated by these costimulatory risk molecules, and the role they may play in inflammatory disease genetics, we carried out gene expression (RNA-seq) and chromatin accessibility (ATAC-seq) profiling of naive and memory CD4+ T cells (N=5 donors) activated via four different costimulatory receptors: CD28 (the standard molecule used for in vitro activation studies), along with alternative costimulatory molecules ICOS, CD6, and CD27. Most, but not all, activation genes and regions are shared by different costimulation conditions. Alternative costimulation induced lower proliferation and cytokine production, but higher lysosome production, altered metabolic processing, and indications of "signal seeking" behaviour (homing and expression of costimulatory and cytokine receptors). We validated a number of these functions at the surface protein level using orthogonal experimental techniques. We found the strongest enrichment of heritability for inflammatory bowel disease in shared regions upregulated by all costimulatory molecules. However, some risk variants and genes were only induced by alternative costimulation, and the impact of these variants on expression were less often successfully mapped in studies of T cells activated by traditional CD28 costimulation. This suggests that future genetics studies of gene expression in activated T cells may benefit from including alternative costimulation conditions.

genomics↗