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

Abstract

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.

Figure 1:. Treg cells promote recovery from lung injury through distinct mechanisms.

Classical Treg cell immunosuppressive functions limit tissue injury by reducing the activation of inflammatory and tissue-destructive immune cells. In addition, Treg cells also limit tissue damage through the induction of tissue-protective programs such as impairing collagen-producing cell activation and proliferation, polarizing macrophages and monocytes toward anti-inflammatory/pro-repair phenotypes, and directly enhancing epithelial resilience. Finally, Treg cells coordinate lung repair through the production of growth factors (GFs) another other soluble mediators that drive epithelial regeneration and vascular recovery. Created with Biorender.com.

Figure 2:. Lung injury and recovery consist of distinct physiologic phases that require discrete Treg cell functions.

Initial tissue injury results in direct pathogen-mediated damage of lung tissue. These inciting events are followed by a period of predominantly immune-mediated tissue damage that continues even after removal of the offending insult (i.e., pathogen clearance). During this ensuing period, reparative processes are activated, yet maximal tissue regeneration will not occur during ongoing inflammation. Treg cells likely use distinct functional programs during these phases; however, few studies have specifically identified specific effector pathways that are required during each phase. Future studies must harness existing genetic tools that allow for modulation of Treg cell function in time and space to identify context-specific tissue-protective and -regenerative Treg cell programs. Time scale shown for common murine influenza models of viral pneumonia. ERT2, tamoxifen-sensitive mutated ligand-binding domain of the human estrogen receptor α. Created with Biorender.com.