Oleic Acid Availability Preprograms Early Thymocytes for Treg Cell Commitment in the Periphery [Rna-seq]. Oleic Acid Availability Preprograms Early Thymocytes for Treg Cell Commitment in the Periphery [Rna-seq]

The natures of activation signals are essential in determining T cell subset differentiation, however, the properties of T cell subset preference acquired during intrathymic development remain elusive. Here we show that naïve CD4+ T cells generated in the thymic microenvironment lacking SCD1, the enzyme catalyzing oleic acid production, exhibit enhanced Treg cell differentiation and confer on mice the ability to resist EAE. SCD1 deletion in K14+ thymic epithelia recapitulated the enhanced Treg cell differentiation phenotype of SCD1 knockout mice. The dearth of oleic acid permitted Dot1L to increase H3K79me2 level at the Atp2a2 locus of thymocytes at the DN2-DN3 transition stage. Such epigenetic modification persisted to naïve CD4+ T cells and facilitated Atp2a2 expression. Upon TCR activation, Atp2a2 enhanced the activity of calcium-NFAT1-Foxp3 axis to promote naïve CD4+ T cells to differentiate into Treg cells. Therefore, oleic acid availability is critical for preprogramming thymocytes with Treg differentiation propensities in periphery. Overall design: RNA-seq data of cTECs (Ly51+ UEA1−) and mTECs (Ly51− UEA1+) derived from SCD1 knockout mice and littermate control mice

激活信号的本质对于决定T细胞亚群分化至关重要，然而胸腺内发育过程中获得的T细胞亚群偏好特性仍不甚明确。本研究显示，在缺乏SCD1（催化油酸生成的酶）的胸腺微环境中产生的初始CD4+ T细胞，其调节性T细胞（Treg cell）分化能力增强，并使小鼠获得抵抗实验性自身免疫性脑脊髓炎（EAE）的能力。在K14阳性胸腺上皮细胞（K14+ thymic epithelia）中敲除SCD1，可重现SCD1敲除小鼠中增强的Treg细胞分化表型。油酸匮乏使得Dot1L在胸腺细胞DN2-DN3过渡阶段的Atp2a2基因座处提升了组蛋白H3赖氨酸79二甲基化（H3K79me2）水平。此类表观遗传修饰可延续至初始CD4+ T细胞，并促进Atp2a2的表达。在T细胞受体（TCR）激活后，Atp2a2可增强钙-NFAT1-Foxp3信号轴的活性，进而促进初始CD4+ T细胞分化为调节性T细胞。因此，油酸的可获得性对于预编程胸腺细胞使其在外周具备Treg细胞分化倾向至关重要。总体实验设计：采集来自SCD1敲除小鼠及其同窝对照小鼠的皮质胸腺上皮细胞（cTECs，Ly51+ UEA1−）与髓质胸腺上皮细胞（mTECs，Ly51− UEA1+）的RNA测序（RNA-seq）数据。