CD25 Treg Functions and Advanced Immune Insights

Regulatory T cells (Tregs) maintain immune balance by suppressing excessive responses and preventing autoimmunity. A key feature of Tregs is the expression of CD25, the alpha chain of the interleukin-2 receptor (IL-2R), which is essential for their function and survival. Understanding CD25’s role in Treg biology provides insights into immune regulation and potential therapies.

Recent research has highlighted the intricate relationship between CD25 signaling, Treg diversity, and immune modulation. Scientists are also investigating antibody-based strategies targeting CD25 for immunotherapy.

CD25 Expression And Treg Characteristics

Tregs are characterized by the transcription factor FOXP3, which governs their suppressive function. Among their defining surface markers, CD25 (IL-2Rα) is particularly significant. Unlike conventional T cells, where its expression is transient and activation-dependent, CD25 is constitutively expressed at high levels on Tregs. This enables them to efficiently capture IL-2, a cytokine indispensable for their survival. The high-affinity IL-2 receptor complex—formed by CD25, CD122 (IL-2Rβ), and CD132 (common gamma chain)—allows Tregs to outcompete other immune cells for IL-2, reinforcing their suppressive capacity.

CD25 is also crucial for Treg stability. Reduced CD25 expression diminishes suppressive activity and increases the likelihood of conversion into pro-inflammatory effector cells, particularly in low-IL-2 environments. Epigenetic modifications, such as demethylation of the Treg-specific demethylated region (TSDR) within the FOXP3 locus, are influenced by CD25-mediated signaling, ensuring Treg identity. Without sustained IL-2 signaling, Tregs may lose their regulatory phenotype, contributing to immune dysregulation.

CD25 also plays a role in Treg metabolism. Unlike conventional T cells, which rely on glycolysis during activation, Tregs favor oxidative phosphorylation and lipid metabolism to sustain function. IL-2 signaling enhances mitochondrial fitness by upregulating genes involved in fatty acid oxidation and oxidative phosphorylation. This metabolic adaptation is especially relevant in tissue-resident Tregs, which must persist in nutrient-limited environments. Disruptions in CD25 expression or IL-2 availability impair these metabolic pathways, leading to Treg dysfunction.

IL-2 Signaling Pathways In Tregs

IL-2 signaling is essential for Treg survival, function, and stability. Unlike conventional T cells, which require IL-2 primarily for proliferation, Tregs depend on continuous IL-2 exposure to maintain their suppressive phenotype. This is mediated through the high-affinity IL-2 receptor, composed of CD25, CD122, and CD132. The constitutive expression of CD25 on Tregs ensures efficient IL-2 capture, driving downstream signaling that regulates gene expression, metabolism, and cellular homeostasis.

Upon IL-2 binding, the IL-2R complex activates Janus kinase 1 (JAK1) and Janus kinase 3 (JAK3), leading to phosphorylation and activation of signal transducer and activator of transcription 5 (STAT5). Phosphorylated STAT5 (pSTAT5) dimerizes and translocates into the nucleus, binding to regulatory elements of FOXP3 and other genes that reinforce Treg identity. The strength and duration of STAT5 activation are critical for sustaining FOXP3 expression. Genome-wide analyses show that pSTAT5 upregulates genes essential for Treg function, including CTLA-4, IL-10, and TIGIT. Impaired STAT5 activation weakens suppressive capacity and increases susceptibility to inflammatory reprogramming.

IL-2 signaling also engages the phosphoinositide 3-kinase (PI3K)-AKT-mTOR pathway, which regulates metabolism and survival. Activation of PI3K leads to phosphorylation of AKT, modulating downstream targets such as forkhead box protein O1 (FOXO1) and mechanistic target of rapamycin (mTOR). FOXO1 is crucial for Treg persistence, controlling genes involved in quiescence and longevity. mTOR integrates environmental cues to regulate metabolic adaptation, particularly in tissue-resident Tregs. While conventional T cells rely on glycolysis, Tregs prioritize oxidative phosphorylation and fatty acid oxidation, a preference reinforced by IL-2-driven mTOR signaling. Dysregulation of this pathway can impair Treg function.

Beyond signaling pathways, IL-2 influences epigenetic modifications that stabilize Treg identity. Sustained IL-2 exposure maintains the demethylation status of the TSDR within the FOXP3 locus, ensuring stable FOXP3 expression. Transient IL-2 deprivation can lead to partial TSDR remethylation, weakening suppressive function and increasing plasticity. Pharmacological interventions that enhance IL-2 signaling, such as low-dose IL-2 therapy, are being explored for autoimmune diseases where Treg dysfunction is implicated.

Treg Diversity In The Immune Network

Tregs are a diverse population that adapts to distinct immunological environments. Their heterogeneity is shaped by factors such as tissue localization, cytokine exposure, and antigen specificity, allowing precise immune modulation. Thymus-derived Tregs (tTregs) form a stable lineage dedicated to immune suppression, while peripherally induced Tregs (pTregs) arise in response to environmental cues, particularly in mucosal tissues where tolerance to commensal microbiota and dietary antigens is necessary. Disruptions in pTreg differentiation are linked to inflammatory disorders like inflammatory bowel disease (IBD) and allergies.

Tissue-resident Tregs exhibit unique transcriptional and metabolic adaptations. In visceral adipose tissue, they express high levels of PPAR-γ, a transcription factor essential for lipid metabolism and immune modulation. These adipose-associated Tregs contribute to metabolic homeostasis by controlling inflammation and promoting insulin sensitivity. Similarly, skin-resident Tregs upregulate ST2, the receptor for IL-33, which enhances survival and function in response to epithelial damage. These specialized regulatory programs enable Tregs to maintain tissue integrity under varying physiological conditions.

Tregs also exhibit functional diversity based on their interactions with other immune cells. CXCR3+ Tregs are enriched in inflamed tissues and effectively suppress Th1-driven responses. In contrast, CCR8+ Tregs are predominantly found in tumor microenvironments, where they promote immune evasion by dampening anti-tumor immunity. The presence of distinct Treg subsets in tumors has fueled interest in targeted therapies. Selective depletion of suppressive Tregs without compromising systemic immune tolerance remains a major challenge in oncology. Identifying molecular signatures that define these subsets is key to developing precise immunotherapies.

Antibody Strategies Targeting CD25

Monoclonal antibodies targeting CD25 are being developed for autoimmunity, transplantation, and cancer immunotherapy. These antibodies primarily function by blocking IL-2 binding to CD25, altering downstream signaling. Their therapeutic effects depend on whether they deplete CD25-expressing cells or selectively interfere with IL-2 signaling without complete cell elimination.

Daclizumab and basiliximab are FDA-approved monoclonal antibodies used in transplantation to prevent organ rejection. By competitively inhibiting IL-2 binding, they reduce T cell activation, lowering the risk of graft rejection. Daclizumab, however, was withdrawn due to severe inflammatory brain disorders. Basiliximab remains in clinical use due to its safety and short half-life, making it suitable for induction therapy.

In oncology, CD25-targeting antibodies aim to enhance anti-tumor immunity. A key challenge is selectively depleting suppressive Tregs in tumors without affecting peripheral immune tolerance. Camidanlumab tesirine, an anti-CD25 antibody-drug conjugate, eliminates CD25-expressing cells via a cytotoxic payload, showing promise in early-phase clinical trials for hematologic malignancies. Another approach involves IL-2 muteins—engineered cytokines that preferentially bind CD122 and CD132 while avoiding CD25, expanding effector T cells without disproportionately stimulating Tregs.