Oleic acid availability impacts thymocyte preprogramming and subsequent peripheral T_reg cell 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 (T_reg) cell differentiation and attenuated development of experimental autoimmune encephalomyelitis. Scd1 deletion in K14⁺ thymic epithelia recapitulated the enhanced T_reg cell differentiation phenotype of Scd1-deficient mice. The dearth of OA permitted DOT1L to increase H3K79me2 levels at the Atp2a2 locus of thymocytes at the DN2-DN3 transition stage. Such epigenetic modification persisted in naive CD4⁺ T cells and facilitated Atp2a2 expression. Upon T cell receptor activation, ATP2A2 enhanced the activity of the calcium-NFAT1-Foxp3 axis to promote naive CD4⁺ T cells to differentiate into T_reg cells. Therefore, OA availability is critical for preprogramming thymocytes with T_reg cell differentiation propensities in the periphery.