Exposing unstable Tregs
The regulatory T cell (Treg) gene expression program is stably maintained by the transcription factor Foxp3, although certain environmental signals can trigger loss of Foxp3 expression and acquisition of an effector phenotype. Using genetic fate mapping and adoptive transfers in mice, Junius et al. demonstrate that fate instability is limited to a subset of Tregs that can be purged through serial exposure to a lymphopenic environment. Tregs lacking neuropilin-1 (Nrp1) expression and displaying a naïve phenotype were transcriptionally related to progeny that had recently lost Foxp3 expression, and Nrp1neg Tregs were enriched for unstable Tregs upon lymphopenic challenge. These results demonstrate that Foxp3+ cells are heterogeneous in their commitment to the Treg lineage, which could be applied to improve the stability of Treg-based cell therapies.
Abstract
Regulatory T cells (Tregs) are indispensable for the control of immune homeostasis and have clinical potential as a cell therapy for treating autoimmunity. Tregs can lose expression of the lineage-defining Foxp3 transcription factor and acquire effector T cell (Teff) characteristics, a process referred to as Treg plasticity. The extent and reversibility of such plasticity during immune responses remain unknown. Here, using a murine genetic fate-mapping system, we show that Treg stability is maintained even during exposure to a complex microbial/antigenic environment. Furthermore, we demonstrate that the observed plasticity of Tregs after adoptive transfer into a lymphopenic environment is a property limited to only a subset of the Treg population, with the nonconverting majority of Tregs being resistant to plasticity upon secondary stability challenge. The unstable Treg fraction is a complex mixture of phenotypically distinct Tregs, enriched for naïve and neuropilin-1–negative Tregs, and includes peripherally induced Tregs and recent thymic emigrant Tregs. These results suggest that a “purging” process can be used to purify stable Tregs that are capable of robust fate retention, with potential implications for improving cell transfer therapy.
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