IL-2, or interleukin-2, is an important cytokine involved in regulating immune responses. It is primarily produced by activated T cells and acts as a growth factor for other immune cells, including cytotoxic T cells and natural killer (NK) cells, promoting their proliferation and activation. IL-2 also supports developing and maintaining regulatory T cells, which are crucial for immune tolerance. 

What is IL-2?

Scientists discovered the IL-2 protein in the 1970s as a key T cell growth factor, fundamentally changing our understanding of how the immune system is molecularly controlled. Like other members of the interleukin cytokine family, it is a small protein that plays an essential role in cell signaling and immune responses. 

IL-2, specifically, is hugely influential in the transcriptional and metabolic determination of T cell proliferation and differentiation.

IL-2 Function in the Immune System

During steady-state immune conditions, IL-2 is primarily produced by activated CD4+ T cells in the lymph tissues and binds to cells in the immediate area that express its receptor, CD25 (also called IL-2Rɑ). Typically, these receptor cells are regulatory T cells (Tregs), and the continuous binding of IL-2 maintains a level of immune homeostasis in the body. However, during an active immune response to a pathogen or cancerous tissue, IL-2 cytokines are produced in large quantities by both activated CD4+ helper T cells and CD8+ cytotoxic T cells. 

IL-2 acts as both a growth factor and an immunomodulator. It stimulates the proliferation and activation of cytotoxic T cells, NK cells, and B cells, enhancing their cell-killing ability. IL-2 cytokine signaling occurs along two major pathways: 

  1. Paracrine signaling happens when the secreted IL-2 binds to neighboring immune cells, stimulating their activation and expansion. 
  2. Autocrine signaling involves IL-2 cytokine binding to the CD25 IL-2 receptor on the same T cell that produced it, promoting its own proliferation. 

The strength and duration of IL-2 signaling impact the expansion of antigen-specific CD8+ cell populations. Weak signaling during the first contact a T cell has with a presented antigen severely reduces expansion while an overwhelming IL-2 response triggers large amounts of short-lived, terminally differentiated effector T cells. Similarly, IL-2 promotes the expansion of helper T cell (CD4+) populations while specifically maintaining helper T cell type 1 (Th1) and helper T cell type 2 (Th2)  differentiation and inhibiting Th17 differentiation. 

IL-2 pathways also affect dendritic cells (DCs), which are important antigen-presenting cells (APCs) for early immune activation. DCs have CD25 receptors on their membranes, allowing them to bind and uptake IL-2 and present it to nearby effector T cells. This process happens early during T cell activation—before the T cells themselves begin to express CD25—and likely influences the T cells’ ability to later bind IL-2 through CD25 expression. 

Applications of IL-2 in Immunotherapy

The versatile actions of IL-2 make it a potential target for therapeutic interventions. Low-dose IL-2 immunotherapy can increase the numbers of Tregs, which can be beneficial in conditions like autoimmunity, chronic inflammation, and graft rejection. 

Conversely, high-dose IL-2 administration may be used to expand cytotoxic lymphocyte populations for the treatment of metastatic cancer. Selective IL-2 immunotherapy can be achieved through improved IL-2 formulations, such as IL-2 bound to specific monoclonal antibodies or modified IL-2 molecules with enhanced affinity for CD25 or CD122 receptors, which supports immune memory.

In some situations, excessive or dysregulated IL-2 signaling can lead to autoimmune disorders. IL-2 inhibitors are used as a therapeutic intervention in these cases. An IL-2 inhibitor is a substance or drug that blocks or dampens IL-2 signaling. 

By inhibiting IL-2 binding, the excessive immune response is controlled, reducing inflammation and preventing damage caused by an overactive immune system. IL-2 inhibitors are used to treat autoimmune diseases, including rheumatoid arthritis and psoriasis, as well as in organ transplantation to prevent rejection by suppressing immune responses. These inhibitors can be monoclonal antibodies or other molecules that specifically target IL-2 or its receptors.

Artificial Manufacture of IL-2 for Cell Therapy

IL-2 can be artificially manufactured for therapeutic use in a laboratory using recombinant DNA technologies. This involves inserting the gene coding for IL-2 production into host organisms, such as bacteria or yeast, which are then grown in large numbers to produce the recombinant IL-2 protein. Drugs like aldesleukin are made this way, specifically engineered for cancer immunotherapy

Aldesleukin is formulated to have consistent purity, potency, and stability, ensuring reliable dosing and administration compared to relying on naturally occurring IL-2 secretion. The recombinant nature of aldesleukin allows for large-scale production, ensuring a steady supply for clinical purposes. Regulatory authorities have approved it as a treatment for certain types of metastatic melanoma and renal cell carcinoma. Adoptive cell therapies, such as CAR-T therapy, may use IL-2-based treatments to enhance anti-tumor effects. 

By administering therapies like aldesleukin, higher than physiological doses of IL-2 can be delivered to patients, promoting the expansion and activation of immune cells, including cytotoxic T cells and natural killer cells, which can enhance the immune system’s ability to target and destroy cancer cells. However, the potent immunostimulatory kinetics that makes it an effective therapy may also lead to significant side effects in some patients. 

Common side effects range from flu-like symptoms and blood count abnormalities to organ toxicity and capillary leak syndrome. Given the potential for severe side effects, therapies like aldesleukin are typically administered in specialized medical settings with close monitoring and supportive care.

Nanotein’s Activators are Compatible with IL-2 Expansion

Interleukin-2 has a long and interwoven history with the development of modern adoptive cell therapies. It serves as both a complementary therapy, like with aldesleukin, and as an important component to the process of T cell activation and expansion ex vivo

Nanotein Technologies’ products have been developed with this in mind. Our CAR-T technology lineup, including the NanoSparkTM STEM-T Soluble T Cell Activator and NanoSpark™ GROW-NK Soluble Activator, is fully compatible with using T cell expansion media supplemented with cytokines like IL-2. 

We have protocols tailor-made for IL-2 use and available for your research needs. Contact our team to learn more. 

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