Oleic acid availability impacts thymocyte preprogramming and subsequent peripheral Tregcell differentiation

The nature of activation signals is essential in determining T cell subset differentiation; however, the features that determine T cell subset preference acquired during intrathymic development remain elusive. Here we show that naive CD4+T cells generated in the mouse thymic microenvironment lacking Scd1, encoding the enzyme catalyzing oleic acid (OA) production, exhibit enhanced regulatory T (Treg) cell differentiation and attenuated development of experimental autoimmune encephalomyelitis. Scd1deletion in K14+thymic epithelia recapitulated the enhanced Tregcell differentiation phenotype of Scd1-deficient mice. The dearth of OA permitted DOT1L to increase H3K79me2 levels at the Atp2a2locus of thymocytes at the DN2–DN3 transition stage. Such epigenetic modification persisted in naive CD4+T cells and facilitated Atp2a2expression. Upon T cell receptor activation, ATP2A2 enhanced the activity of the calcium–NFAT1–Foxp3 axis to promote naive CD4+T cells to differentiate into Tregcells. Therefore, OA availability is critical for preprogramming thymocytes with Tregcell differentiation propensities in the periphery.