Regulatory T cells (T_regs) are indispensable for the control of immune homeostasis and have clinical potential as a cell therapy for treating autoimmunity. T_regs can lose expression of the lineage-defining Foxp3 transcription factor and acquire effector T cell (T_eff) characteristics, a process referred to as T_reg plasticity. The extent and reversibility of such plasticity during immune responses remain unknown. Here, using a murine genetic fate-mapping system, we show that T_reg stability is maintained even during exposure to a complex microbial/antigenic environment. Furthermore, we demonstrate that the observed plasticity of T_regs after adoptive transfer into a lymphopenic environment is a property limited to only a subset of the T_reg population, with the nonconverting majority of T_regs being resistant to plasticity upon secondary stability challenge. The unstable T_reg fraction is a complex mixture of phenotypically distinct T_regs, enriched for naïve and neuropilin-1–negative T_regs, and includes peripherally induced T_regs and recent thymic emigrant T_regs. These results suggest that a “purging” process can be used to purify stable T_regs that are capable of robust fate retention, with potential implications for improving cell transfer therapy.

调节性 T 细胞 (T _regs ) 对于控制免疫稳态是必不可少的，并且具有作为治疗自身免疫的细胞疗法的临床潜力。T _regs可以失去谱系定义 Foxp3 转录因子的表达并获得效应 T 细胞 (T _eff ) 特征，这一过程称为 T _reg可塑性。在免疫反应过程中这种可塑性的程度和可逆性仍然未知。在这里，我们使用小鼠遗传命运图谱系统，表明即使在暴露于复杂的微生物/抗原环境期间，T _{reg的稳定性也得以保持。}此外，我们证明了观察到的 T _{regs的可塑性}在过继转移到淋巴细胞减少的环境中后，这种特性仅限于 T _reg群体的一部分，大多数T _reg在二次稳定性挑战时对可塑性具有抗性。不稳定的 T _reg部分是表型不同的 T reg 的复杂混合物_，富含幼稚和 neuropilin-1 阴性 T _reg，包括外周诱导的 T _reg和最近的胸腺迁移 T _reg。这些结果表明，“清除”过程可用于纯化稳定的 T _regs，这些 T regs 能够稳定地保留命运，对改善细胞转移治疗具有潜在意义。