Discovery of Regulatory T Cells and Their Prospective Therapeutic Applications
Year: 2025
Type: article
Abstract: Regulatory T cells (Treg cells) are a specialized subset of CD4+ T cells defined by expression of the lineage-specifying transcription factor FOXP3 and a potent capacity to maintain peripheral immune tolerance. The modern concept of Tregs was catalyzed by Shimon Sakaguchi’s identification of CD4+CD25+ suppressive T cells and subsequent work establishing FOXP3 as a central determinant of Treg cell development and function; together with landmark FOXP3 genetic discoveries by Mary E. Brunkow and Fred Ramsdell, these advances transformed understanding of immune homeostasis and were recognized by the 2025 Nobel Prize in Physiology or Medicine. Under normal physiological conditions, FOXP3+ Treg cells restrain autoreactive lymphocytes, prevent excessive inflammation, and shape antigen-presenting cell activity through contact-dependent pathways and suppressive cytokines, thereby protecting tissues from immune-mediated damage. Disruption of Treg abundance, stability, or suppressive capacity can therefore lead to immune dysregulation and disease. Over the past two decades, Treg cells have become a major focus of immunology because their roles are highly context-dependent. In autoimmune and chronic inflammatory diseases, impaired Treg cell function or insufficient Treg activity contributes to loss of tolerance and persistent tissue injury, supporting therapeutic approaches designed to enhance Treg cell number, stability, and suppressive potency. In contrast, many cancers exploit Treg cells by promoting their expansion, activation, and recruitment into the tumor microenvironment (TME), where they blunt antitumor immunity by suppressing cytotoxic T-cell priming and effector function, limiting dendritic cell activation, and fostering immune escape. In both settings, immune checkpoint pathways critically influence Treg cell biology. Beyond PD-1/PD-L1 and CTLA-4, emerging checkpoints and costimulatory receptors, including TIGIT, TIM-3, LAG-3, and OX40, modulate Treg cell generation, stability, and suppressive functions, thereby shaping the balance between tolerance and immunity. Meanwhile, immunometabolic adaptations further tune Treg cell fitness and function in inflamed tissues and tumors; lipid utilization and mitochondrial programs, among other metabolic axes, enable Treg cells to persist in nutrient- and oxygen-restricted microenvironments, while microenvironmental stress can drive functional remodeling or fragility in a subset-dependent manner. In this review, we summarize the discovery and defining biological features of Treg cells, highlight core suppressive mechanisms and regulatory circuits, and synthesize evidence for the dual roles of Treg cells in preventing autoimmunity yet enabling tumor immune evasion. We further outline current and emerging therapeutic strategies aimed at augmenting Treg cell activity to restore tolerance in autoimmune disease, or selectively depleting, functionally inhibiting, and reprogramming tumor-resident Treg cells to enhance cancer immunotherapy. Overall we discuss how deeper insight into Treg heterogeneity, checkpoint control, and immunometabolic regulation may enable more precise Treg cell-directed interventions and inform next-generation immunotherapeutic combinations across immune-mediated and malignant diseases.
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W7117461948
FWCI:
Cites:
Cited by:
Related to: