Little “Life” Makes Sense (II) | Double Agent—Treg
Release Date:
2023-08-03 17:44
Introduction to Treg Cells
Regulatory T cells (also known as Tregs) are a subset of T cells that play a critical role in modulating or suppressing the activity of other immune cells. Tregs regulate immune responses to both self-antigens and foreign antigens, thereby helping to prevent autoimmune diseases. Based on their developmental origin and functional characteristics, Tregs can be classified into two main subsets: natural regulatory T cells (nTregs) and inducible regulatory T cells (iTregs). Both subsets broadly express the transcription factor Foxp3. nTregs develop naturally in the thymus, where their suppressive function is mediated through direct cell–cell contact, whereas iTregs arise from naïve peripheral T cells that are induced by microenvironmental signals in the tumor microenvironment, including tumor-associated antigens, cytokines such as TGF-β, and other soluble factors.
Regulatory T cells (Tregs) suppress aberrant or excessive immune responses against both self- and non-self-antigens, thereby maintaining immune homeostasis. In tumor immunity, Treg cells contribute to tumorigenesis and progression by inhibiting anti-tumor immune responses.
Regulatory T cells (Tregs), as a critical mechanism for maintaining immune homeostasis and immune tolerance, play an indispensable role in tumor immune regulation and are currently a major research focus in this field, primarily as potential therapeutic targets. Tregs can suppress the activation and differentiation of CD4+ helper T cells and CD8+ cytotoxic T cells, thereby dampening responses against self-antigens and tumor-associated antigens. Within the tumor microenvironment (TME), Tregs can be induced to differentiate from conventional T cells and exhibit potent immunosuppressive functions, which inhibit anti-tumor immunity and promote tumorigenesis and progression. Moreover, Tregs can inhibit the function of effector immune cells through multiple mechanisms, making them a key factor in tumor immune evasion.
Treg cell differentiation
From a differentiation perspective, Treg cells are further classified into naïve Tregs (nTregs), central memory Tregs (cmTregs), effector memory Tregs (emTregs), and effector Tregs (eTregs).
Treg cell differentiation
Treg suppression mechanism
Treg cells can suppress a variety of immune cells, including B cells, NK cells, NKT cells, CD4+ and CD8+ T cells, as well as monocytes and dendritic cells (DCs).
Treg exerts suppressive functions on diverse cell types, including CD4+ and CD8+ T cells, macrophages, dendritic cells (DCs), natural killer (NK) cells, and B cells, through a variety of contact-dependent and contact-independent mechanisms. From a functional perspective, these potential inhibitory mechanisms can be categorized into four “modes of action”: (A) metabolic disruption, (B) release of suppressive cytokines, (C) cell lysis, and (D) targeting antigen-presenting cells (APCs).
The functional heterogeneity of Treg populations reflects the broad spectrum of suppressive mechanisms by which Tregs regulate diverse types of immune responses. These mechanisms can generally be categorized as contact-dependent and humoral, as well as antigen-specific or non-specific. Many of these mechanisms are both universal and complementary, while others are specific to particular types of immune responses.
Treg suppression mechanism
CD127 and Foxp3
Natural Tregs express the CD4+ T-cell co-receptor and CD25 (a component of the IL-2 receptor); therefore, Tregs are predominantly CD4+CD25+. The expression of the nuclear transcription factor Foxp3 is a defining characteristic that governs the development and function of natural Tregs.
Foxp3 is essential for maintaining immune tolerance. Naturally occurring mutations in the Foxp3 gene can give rise to autoreactive lymphocytes, leading to the rare but severe human disease IPEX (immunodysregulation, polyendocrinopathy, and enteropathy) and to “scaly skin” in mice.
Studies have shown that in purified CD4+CD25+ cells, the expression of CD127 is negatively correlated with that of Foxp3. Foxp3 is currently recognized as the most specific marker for Tregs; however, because it is intracellular, its detection requires cell fixation and permeabilization, whereas CD127 is a cell-surface marker and does not require such procedures.
Targeting Treg Cells in Cancer Immunotherapy
In TME, a higher abundance of Treg cells and a lower CD8+ T cell-to-Treg cell ratio are associated with poor prognosis, suggesting that Treg cells suppress tumor antigen–specific T cell responses. Therefore, depletion of Treg cells or modulation of their function represents a promising immunotherapeutic strategy.
Depletion of Treg cells enhances anti-tumor immune responses and facilitates tumor eradication in mouse models. Importantly, a preliminary study has shown that Treg cell depletion induces tumor regression in some tumor cell lines but not in others.
Another approach to targeting Treg cells involves controlling or modulating their function and infiltration. In particular, manipulating the chemokine and/or cytokine axes, intracellular signaling pathways, or metabolites within the tumor microenvironment (TME) can induce relative changes in Treg cell function and infiltration.
The Future and Prospects of Treg Cell Therapy
The immunosuppressive activity of Tregs in tumors represents a major barrier to effective antitumor immunity. Combining Treg-targeted therapies with immune checkpoint blockade, immune agonists, cancer vaccines, radiotherapy, and chemotherapy can yield synergistic antitumor effects. However, assessing Treg function in tumor tissues is complex and challenging due to the production of cytokines and chemokines within the tumor microenvironment, as well as foreign-body–induced reprogramming. Early efforts in Treg-directed cancer immunotherapy have primarily focused on Treg depletion, but the outcomes have been suboptimal. Several factors may account for this limitation: first, concomitant depletion of Tregs also removes conventional effector T cells, leading to a marked decline in systemic antitumor immunity; second, Treg depletion is often transient, with Treg levels rapidly rebounding to pre-depletion levels. Therefore, further research into the roles and functions of Tregs is essential to fully harness their potential as an immunotherapeutic target and to develop novel strategies for cancer immunotherapy.
Hycells Biotechnology offers Treg-related services.
Treg sorting service
Hycells provides CD4+CD25+CD127 purified from freshly isolated PBMCs using an immunomagnetic bead-based sorting protocol. LOW of Treg cells.
| Service Number | Service Name |
| W-hPBnTreg-05C | Frozen hPBnTreg cells, Separate Service, 0.5 million |
| W-hPBnTreg-01C | Frozen hPBnTreg cells, Separate Service, 1 million |
| W-hPBnTreg-02C | Frozen hPBnTreg cells, Separate Service, 2 million |
Treg Expansion Service
Hycells Biotechnology offers services for the activation of freshly sorted Tregs using CD3/CD28 agonists and IL-2 expansion, ensuring that the expanded Tregs retain their activity and functional capacity.
| Service Number | Content |
| W-hPBnTregA-02C | Frozen hPBnTreg cells Activating and Augmenting Services, 2 million |
| W-hPBnTregA-05C | Frozen hPBnTreg cells Activating and Augmenting Services, 5 million |
| W-hPBnTregA-10C | Frozen hPBnTreg cells Activating and Augmenting Services, 10 million |
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