Follicular regulatory T (Tfr) cells differentiate from conventional regulatory T (Treg) cells and suppress excessive germinal center (GC) responses by acting on both GC B cells and T follicular helper (Tfh) cells. Here, we examined the impact of mTOR, a serine/threonine protein kinase that senses and integrates diverse environmental cues, on the differentiation and functional competency of Tfr cells in response to protein immunization or viral infection. By genetically deleting Rptor or Rictor, essential components for mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), respectively, we found that mTORC1 but not mTORC2 is essential for Tfr differentiation. Mechanistically, mTORC1-mediated phosphorylation of the transcription factor STAT3 induced the expression of the transcription factor TCF-1 by promoting STAT3 binding to the Tcf7 5′-regulatory region. Subsequently, TCF-1 bound to the Bcl6 promoter to induce Bcl6 expression, which launched the Tfr cell differentiation program. Thus, mTORC1 initiates Tfr cell differentiation by activating the TCF-1-Bcl-6 axis during immunization or infection.

滤泡调节性T （ Tfr中）细胞从常规的调节性T分化（ Treg细胞）的细胞和抑制过度生发中心（ GC ）通过作用于GC B细胞和T滤泡辅助两种反应（ TFH ）细胞。在这里，我们检查了mTOR（一种感应并整合各种环境线索的丝氨酸/苏氨酸蛋白激酶）对Tfr细胞响应蛋白质免疫或病毒感染的分化和功能能力的影响。通过基因删除Rptor或Rictor，mtor复杂1 （ mTORC1 ）的重要组成部分。和mTOR complex 2 （ mTORC2 ），我们发现mTORC1而非mTORC2对Tfr的分化至关重要。从机制上讲，转录因子STAT3的mTORC1介导的磷酸化通过促进STAT3与Tcf7 5'调控区的结合来诱导转录因子TCF-1的表达。随后，TCF-1与Bcl6启动子结合以诱导Bcl6表达，从而启动了Tfr细胞分化程序。因此，mTORC1通过在免疫或感染过程中激活TCF-1-Bcl-6轴来启动Tfr细胞分化。