S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate.

R-2-hydroxyglutarate accumulates to millimolar levels in cancer cells with gain-of-function isocitrate dehydrogenase 1/2 mutations. These levels of R-2-hydroxyglutarate affect 2-oxoglutarate-dependent dioxygenases. Both metabolite enantiomers, R- and S-2-hydroxyglutarate, are detectible in healthy individuals, yet their physiological function remains elusive. Here we show that 2-hydroxyglutarate accumulates in mouse CD8+ T cells in response to T-cell receptor triggering, and accumulates to millimolar levels in physiological oxygen conditions through a hypoxia-inducible factor 1-alpha (HIF-1α)-dependent mechanism. S-2-hydroxyglutarate predominates over R-2-hydroxyglutarate in activated T cells, and we demonstrate alterations in markers of CD8+ T-cell differentiation in response to this metabolite. Modulation of histone and DNA demethylation, as well as HIF-1α stability, mediate these effects. S-2-hydroxyglutarate treatment greatly enhances the in vivo proliferation, persistence and anti-tumour capacity of adoptively transferred CD8+ T cells. Thus, S-2-hydroxyglutarate acts as an immunometabolite that links environmental context, through a metabolic-epigenetic axis, to immune fate and function

Castleman's disease of the leptomeninges

✓ Castleman's disease is a rare, benign lymphoproliferative disorder that usually arises in lymph nodes, most commonly in the mediastinum. The authors report the clinical and pathological features of three patients with localized Castleman's disease of the leptomeninges. There were two women, aged 63 and 82 years, and one 25-year-old man. Two patients had progressive focal motor seizures of 3 and 24 months' duration, and the third patient presented acutely with generalized seizures. The clinical diagnosis was meningioma in each case, based on computerized tomography scans, cerebral arteriography, and the operative findings. All three lesions arose in the leptomeninges, compressed the underlying cerebral cortex, and infiltrated the overlying dura to a variable extent. Surgical excision of the tumor resulted in marked clinical improvement in all three patients. Histologically, two cases were classified as the hyaline-vascular type and one as the plasma cell type. Immunohistochemical stains of the latter case revealed a monoclonal population of mature plasma cells. Only a few scattered polyclonal plasma cells were seen in the other two cases. The authors conclude that Castleman's disease involving the leptomeninges is a rare disorder that may mimic meningioma clinically and radiographically.</jats:p