Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Proc Natl Acad Sci U S A. 2024 Mar 12;121(11):e2317658121. doi: 10.1073/pnas.2317658121. Epub 2024 Mar 4.
Identification of mechanisms that program early effector T cells to either terminal effector T (T) or memory T (T) cells has important implications for protective immunity against infections and cancers. Here, we show that the cytosolic transcription factor aryl hydrocarbon receptor (AhR) is used by early T cells to program memory fate. Upon antigen engagement, AhR is rapidly up-regulated via reactive oxygen species signaling in early CD8 T cells, which does not affect the effector response, but is required for memory formation. Mechanistically, activated CD8 T cells up-regulate HIF-1α to compete with AhR for HIF-1β, leading to the loss of AhR activity in HIF-1α short-lived effector cells, but sustained in HIF-1α memory precursor effector cells (MPECs) with the help of autocrine IL-2. AhR then licenses CD8 MPECs in a quiescent state for memory formation. These findings partially resolve the long-standing issue of how T cells are regulated to differentiate into memory cells.
鉴定将早期效应 T 细胞编程为终末效应 T（T）或记忆 T（T）细胞的机制，对于预防感染和癌症的保护性免疫具有重要意义。在这里，我们表明，胞质转录因子芳香烃受体（AhR）被早期 T 细胞用于编程记忆命运。在抗原结合后，AhR 通过早期 CD8 T 细胞中的活性氧信号迅速上调，这不会影响效应应答，但对于记忆形成是必需的。在机制上，激活的 CD8 T 细胞上调 HIF-1α，以与 AhR 竞争 HIF-1β，导致 AhR 活性在 HIF-1α 短寿命效应细胞中丧失，但在 HIF-1α 记忆前体效应细胞（MPECs）中由于自分泌 IL-2 的帮助而持续存在。然后，AhR 使 CD8 MPECs 处于静止状态以形成记忆。这些发现部分解决了长期以来关于 T 细胞如何被调节分化为记忆细胞的问题。
