Regulatory T cells (Tregs) are vital in immune control. On Aug 8, 2023, Innovent Biologics company published a article in Nature Cancer regarding "IL-2Rα-biased agonist boosts tumor-fighting CD25+CD8+T cells". The study unveils early insights into IBI363, a dual-specific antibody fusion (PD-1/IL-2) mechanism [1]. Tregs, as a specialized group in T cells, actively maintains immune balance and tolerance. Among various Tregs types like CD4+CD25+Tregs, CD8+CD25+Tregs, and CD8+CD28+Tregs, CD4+CD25+Tregs have received significant attention.
CD4+CD25+Tregs act as negative regulators, crucial for controlling immune balance. CD25 (also termed IL2RA) forms one component of the high-affinity heterotrimeric interleukin 2 (IL2) receptor (IL2-IL2R-αβγ) on activated T cells. Numerous studies suggested that CD4+CD25+Tregs holds promise for treating immune disorders. Notably, IL-2Rα/IL2RA (CD25), a key marker for CD4+CD25+Tregs, is central in immune research.
1. What are CD4+CD25+Regulatory T cells?
5. The Clinical Potential of IL2RA Targeted Therapy
6. CUSABIO IL2RA Recombinant Proteins & Antibodies for Research Use
CD4+CD25+ Regulatory T cells (CD4+CD25+Tregs) constitute a specific subset of T lymphocytes characterized by the expression of CD25, also known as the IL-2 receptor alpha chain (IL2Rα/IL2RA). In 1995, Sakaguchi et al. were the first to identify a distinct subpopulation of CD4+T lymphocytes consistently displaying elevated levels of CD25 in peripheral blood and spleen tissues of both humans and mice. This groundbreaking discovery marked the initial isolation of CD4+CD25+Tregs. Additional markers, including FOXP3, CTLA-4, and GXTR, are now recognized as unique identifiers for this subset. These markers play a crucial role in distinguishing CD4+CD25+Tregs from activated, effector, and memory T cells (Figure 1) [2-6].
Figure 1. IL2RA/CD25 is involved in the development of Tregs [2]
IL-2Rα/IL2RA, or CD25, is the alpha chain of the interleukin 2 (IL-2) receptor. It belongs to the low-affinity IL-2 receptor group with a concise cytoplasmic region. IL2RA is a primary marker for regulatory T cells due to its consistent and high expression on both resting and active regulatory T cells. Although IL-2 is crucial for signaling through the IL-2 receptor pathway, it can't efficiently control T cell growth with only the IL-2Rβ (CD122) and IL-2Rγ (CD132) dimeric forms. Therefore, IL-2Rα collaborates with IL-2Rβ and IL-2Rγ to form a receptor complex, enhancing IL-2's binding to the receptor (Figure 2) [7-11].
IL2RA (CD25) is mainly on CD4+T cells surfaces, helping regulate regulatory CD4+T cells growth, especially when IL-2 is low. Researchers are increasingly interested in unique CD4+CD25+Tregs subtypes. CD25 in CD4+CD25+Tregs cells is vital for IL-2 response and immune modulation. Treg cells inhibit effector T cell activation without specific targets. IL2RA (CD25) not only marks Treg cells but also empowers them for vital immune functions [7-11].
Figure 2. The structure of IL-2 in complex with IL2Rαβγ receptors [11]
IL-2Rα/IL2RA (CD25) is the alpha component of the IL-2 receptor complex, working with the β and γ chains. It activates downstream signaling by binding non-receptor protein tyrosine kinases, engaging three pathways (Figure 3) [12-14]:
i) Jak-STAT pathway: Jak kinase activation leads to the phosphorylation of the Jak protein-binding region within IL-2R intracellular, initiating STAT into the nucleus, where special genes control cell proliferation and apoptosis.
ii) MAP pathway: Jak and Syk kinase activation phosphorylates IL-2R, setting off a cascade with Shc and Grb-2 proteins. This activates Raf-1 serine/threonine kinase. Jak kinase triggers Pyk2 kinase, launching the MAP pathway. This pathway controls protein-dependent kinases in the cell cycle, boosting cell proliferation.
iii) PI3K pathway: Jak, Pyk2, and lck kinases initiate this pathway. Phosphatidylinositol-3-kinase binds to Shc protein, activating oncogenes Akt and p70S6k. These genes influence apoptotic and proliferative activities.
Figure 3. IL-2/IL2RA signaling pathway [12]
IL2RA (CD25) is a vital marker for Treg cells, serving to both identify and facilitate essential immune regulation. The presence of CD25 on CD4+CD25+Tregs competes with effector cells for IL-2, effectively dampening their growth signals. CD4+CD25+Tregs exhibit two primary functions: immunocompetence, meaning they do not respond to antigen stimulation; immunosuppression, where they mitigate immune responses [13-14].
Recent research highlights that other factors come into play for CD4+CD25+Tregs, including cytokines (IL-10, TGF-β, IL-2, IL-6) and specific cell membrane molecules (CTLA-4, GITR) (Figure 4) [15-18]. The precise mechanism of CD4+CD25+Tregs in immunosuppression is not fully elucidated. Early studies suggest that their inhibitory effects involve direct cell-to-cell contact [18].
Figure 4. IL-10 and TGF-β involved in immune responses of CD4+CD25+Tregs (iTREG) [16]
IL2RA, or CD25, is mainly on CD4+CD25+Tregs’ surface. These newly identified T-cell subtypes have a unique role in immune control, maintaining tolerance and regulating responses. Thus, CD4+CD25+Tregs subtype has gained increasing attention in recent years.
Growing evidence suggests that abnormalities in CD4+CD25+Tregs cells, both in numbers and function, play a vital role in disrupting autoimmune tolerance and triggering various autoimmune diseases. For instance, patients with type I diabetes have significantly fewer CD4+CD25+Tregs cells in their blood, which worsens with disease severity. These cells not only lose their immune-suppressing abilities but can also produce more IFN-γ and less IL-10. In certain cases, even if T cell numbers remain relatively steady, their ability to curb T cell growth weakens. This, along with changes in cytokine release, leads to a diminished protective function of CD4+CD25+Tregs, impacting the defense of pancreatic islets [19-20].
In systemic lupus erythematosus (SLE), the ratio of CD4+CD25high T cells to CD4+CD25int T cells in the peripheral blood of patients is reduced, suggesting that there is an immune imbalance manifested by elevated effector T cells and reduced immunosuppression. By increasing the number and function of CD4+CD25high T cells or suppressing effector T cells could be a therapeutic target for SLE [21]. In other autoimmune diseases such as multiple sclerosis [22], rheumatoid arthritis [23], psoriasis [24], Wegner's granulomatosis [25], and myasthenia gravis [26], the immunosuppressive activity of CD4+CD25+Tregs is decreased or deficient, although their numbers are normal.
CD4+CD25+Tregs play a key role in graft-versus-host disease (GVHD), a common immune disorder linked with allogeneic hematopoietic stem cell transplantation. Research indicates that CD4+CD25+Tregs can influence GVHD development. GVHD risk rises when CD4+CD25+Tregs are removed from donor lymphocytes or recipients, while infusing fresh donor CD4+CD25+Tregs lessens GVHD. Notably, CD4+CD25+CD62L+Tregs have a significant regulatory impact on acute GVHD. Various CD4+CD25+Treg subpopulations hold distinct roles in suppressing GVHD. These findings offer valuable insights for clinically preventing and treating GVHD [27-28].
Many tumor antigens are like "self" markers. Namely, some tumor antigens mimic self-markers, potentially leading to immune system confusion. CD4+CD25+Tregs act as immune regulators by stopping T cells from attacking both foreign and self antigens. This helps tumors avoid being targeted by the immune system, while still keeping the body's normal cells safe [29-30]. For example, in acute myeloid leukemia (AML), leukemia cells from CD25+AML patients show high levels of myeloid antigens (CD11b, CD36), lymphoid antigens (CD4, CD22, CD123), and low levels of plasma cell antigens (CD38) and NK cell antigen (CD56) [31-32].
In ovarian cancer, tumor cells release a signal that attracts CD4+CD25+Tregs to the tumor site, which then gather in the cancerous tissue. This makes it hard for the immune system to attack the tumor [33-34]. Researchers are exploring ways to target these Tregs to enhance the immune response against tumors.
CD4+CD25+Tregs suppress the immune response against H. pylori, allowing it to harm the stomach and duodenum, potentially leading to ulcers and cancer [35]. Genetic variations in the IL2RA gene (rs3118470) are linked to family history of stomach issues and disease severity [36]. In pregnant mice, CD4+CD25+Tregs are higher in spleens, ileocecal lymph nodes, and blood, suggesting their role in maternal-fetal immune tolerance. Blocking CD25 with antibodies can lead to abortion [37].
In a rat model of cerebral ischemia-reperfusion, CD4+CD25+Tregs infusion reduced cerebral infarction size in middle cerebral artery occlusion and reperfusion (MCAO/R), improved neurological outcomes, and protected oligodendrocytes and axons, reducing white matter injury after cerebral ischemia [38].
Several companies are developing drugs that target IL2RA (also known as CD25). These companies include Sunshine Guojian Pharmaceuticals, Innovent Biologics, Inc., Ligand Pharmaceuticals, Inc., Eisai Co., Ltd., and Novartis Pharma AG etc. Currently, three approved drugs focusing on IL2RA/CD25 are on market for kidney transplants and specific cancers therapy. Some clinical trials are in-progress, such as Inolimomab, which are nearing approval for treating Graft Versus Host Disease (GVHD), hold significant promise. CD4+CD25+Tregs, is considered as a specialized type of immune cells that control immune responses. Thus, investigating IL2RA (CD25) and its connection in regulatory T cells has the potential to reveal novel therapeutic approaches for specific diseases.
CD25, or IL2RA, is a key protein found on the surface of certain immune cells called CD4+CD25+Tregs. These cells play a vital role in maintaining immune balance by suppressing excessive immune responses. CD25's presence helps identify and regulate these Tregs. Abnormalities in CD25 function have been linked to autoimmune diseases, ulcers, and cancer. Researchers are exploring CD25-targeting drugs for immune-related disorders. Gaining insight into the importance of CD25/IL2RA provides valuable information about immune regulation and possible treatment approaches.
To fully support researchers and pharmaceutical companies in their research on IL2RA in autoimmune diseases, tumors, or other diseases, CUSABIO presents IL2RA active proteins & antibodies to support your research on the mechanism of IL2RA or its potential clinical value.
CUSABIO IL2RA (CD25) protein
Purity was greater than 95% as determined by SDS-PAGE. (Tris-Glycine gel) Discontinuous SDS-PAGE (reduced) with 5% enrichment gel and 15% separation gel.
Immobilized Human IL2RA at 2μg/mL can bind Anti-IL2RA recombinant antibody (CSB-RA011649MA1HU), the EC50 is 2.463-3.353 ng/mL.
Immobilized Human IL2RA at 2μg/mL can bind Human IL2 (CSB-MP011629HU), the EC50 is 1.693-2.039 ng/mL.
CUSABIO IL2RA (CD25) antibody
IL2RA Recombinant Monoclonal Antibody (Code: CSB-RA011649MA1HU)
References
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