Regulatory T cells: masterminds of immune equilibrium and future therapeutic innovations

Abstract

Regulatory T cells (Tregs), a subset of CD4⁺T cells marked by the expression of the transcription factor forkhead box protein 3 (Foxp3), are pivotal in maintaining immune equilibrium and preventing autoimmunity. In our review, we addressed the functional distinctions between Foxp3⁺Tregs and other T cells, highlighting their roles in autoimmune diseases and cancer. We uncovered the dual nature of Tregs: they prevented autoimmune diseases by maintaining self-tolerance while contributing to tumor evasion by suppressing anti-tumor immunity. This study underscored the potential for targeted therapeutic strategies, such as enhancing Treg activity to restore balance in autoimmune diseases or depleting Foxp3⁺Tregs to augment anti-tumor immune responses in cancer. These insights laid the groundwork for future research and clinical applications, emphasizing the critical role of Foxp3⁺Tregs in immune regulation and the advancement of next-generation immunotherapies.

Keywords: Treg; autoimmune diseases; cancer; checkpoint inhibitors; immunotherapy.

Figure 1

Heterogeneity of Treg subtypes. Treg cells comprise several subtypes based on their origin and function. tTregs are produced in the thymus, where they help maintain self-tolerance by inhibiting self-reactive T cells and facilitating central tolerance to self-antigens. pTregs are induced in peripheral lymphoid organs, mediating peripheral tolerance and regulating the intensity and scope of immune reactions. T_fr cells are enriched in lymph node follicles and splenic follicles, where they regulate B cell activation and antibody production within follicles, thus contributing to the regulation of humoral immune responses. Tr1 cells are distributed throughout peripheral tissues and lymphoid organs, producing abundant IL-10 and TGF-β to restrain immune cell activation and inflammation. tr-Tregs include subpopulations residing in tumor tissues, inflammatory tissues, and organ-specific tissues, regulating local immune responses and impacting tumor development, inflammation progression, and organ immune balance. CD103 and CD69 are classical markers of tr-Tregs, which may be upregulated in TI-Tregs.

Figure 2

Tregs immunoregulation. Treg cells interact with diverse cells in the immune microenvironment to regulate immune stability and foster suppression within the TME. By expressing suppressive receptors and releasing inhibitory cytokines, Treg cells modulate the activation and differentiation of T_eff cells, helping to restrain excessive immune reactions and prevent autoimmune conditions, while also governing immune cell-driven tumor control. Concurrently, other immune cells support Treg activation, proliferation, and functionality, collectively maintaining immune equilibrium.

Figure 3

The equilibrium between Tregs and other immune cells is disrupted in autoimmune disorders. As depicted in the schematic, various cytokines contribute to the initiation and generation of different cell types. Red arrows indicate promotion, while red lines represent inhibition.