Toward a Paradigm to Distinguish Distinct Functions of FOXP3⁺ Regulatory T Cells

FOXP3⁺ regulatory T (Treg) cells are a unique subset of CD4⁺ T cells that classically function as master regulators of immune homeostasis. Besides this canonical suppressive role, which is required to maintain self-tolerance, a growing body of literature has identified Treg cells as critical orchestrators of tissue protection during acute stress and as effector cells that drive repair following tissue injury. Despite substantial interest in these distinct roles, the field has struggled to disentangle Treg cell suppressive functions from those that promote tissue defense and repair. In this article, we will examine the literature in the context of specific physiologic settings, contrasting the suppressive function of Treg cells with their emerging roles in promoting tissue homeostasis and tissue repair. Further, we will discuss a new paradigm differentiating tissue defense from tissue repair−a paradigm needed to translate Treg cell–based therapies to the clinic. ImmunoHorizons, 2021, 5: 944–952.