# Interleukin 2

**Interleukin 2** (IL-2) is a cytokine, a signaling protein of about 15.5 kDa, that is produced by activated T lymphocytes and drives the proliferation, differentiation, and survival of immune cells through its specific cell-surface receptor. It was first identified in 1976 as T-cell growth factor (TCGF) and became the first cytokine shown to have therapeutic benefit, approved as the drug aldesleukin for metastatic renal cell carcinoma and metastatic melanoma.<sup>[1](https://irp.nih.gov/accomplishments/discovery-of-interleukin-2-il-2)</sup><sup> • </sup><sup>[2](https://discovery.dundee.ac.uk/ws/portalfiles/portal/20704755/Signaling_and_Function_of_Interleukin_2_in_T_lymphocytes_Ross_Cantrell_2018.pdf)</sup><sup> • </sup><sup>[3](https://ccr.cancer.gov/sites/default/files/landmarks_2017_web-508.pdf)</sup>

| Key fact | Detail |
|---|---|
| Identity | A 15.5 kDa variably glycosylated globular protein, originally called T-cell growth factor (TCGF)<sup>[2](https://discovery.dundee.ac.uk/ws/portalfiles/portal/20704755/Signaling_and_Function_of_Interleukin_2_in_T_lymphocytes_Ross_Cantrell_2018.pdf)</sup> |
| Discovery | 1976, by IRP researchers led by Robert Gallo, who grew T cells in culture for more than nine months using the factor<sup>[1](https://irp.nih.gov/accomplishments/discovery-of-interleukin-2-il-2)</sup> |
| Receptor | Three subunits: IL-2Rα (CD25), IL-2Rβ (CD122), and the common gamma chain γc (CD132); the trimeric high-affinity receptor binds IL-2 with K<sub>d</sub> ≈ 10<sup>−11</sup> M<sup>[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7037245/)</sup><sup> • </sup><sup>[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC6472684/)</sup> |
| Dose-dependent effects | Low doses preferentially expand regulatory T (Treg) cells; high doses promote effector cells such as CD8<sup>+</sup> T cells and natural killer (NK) cells<sup>[6](https://onlinelibrary.wiley.com/doi/full/10.1002/iid3.1165)</sup> |
| Approved drug | Aldesleukin (Proleukin), initial U.S. approval 1992, for adults with metastatic renal cell carcinoma and metastatic melanoma, given as 600,000 IU/kg every 8 hours up to 14 doses per cycle<sup>[7](https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/103293s51%2C54lbl.pdf)</sup> |
| Main toxicity | Boxed warning for capillary leak syndrome, neurologic toxicity, and serious infections; administration requires a hospital intensive care setting<sup>[7](https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/103293s51%2C54lbl.pdf)</sup> |
| Low-dose use | Under study for autoimmune diseases; in SLE meta-analysis, 54.8% of patients achieved distinct clinical remission with no serious adverse events reported<sup>[6](https://onlinelibrary.wiley.com/doi/full/10.1002/iid3.1165)</sup> |

## Discovery

In the 1970s, researchers trying to determine whether retroviruses cause human disease first needed a way to grow T lymphocytes in the laboratory. A team at the NIH Intramural Research Program led by [Robert Gallo](https://www.edgepedia.org/robert-gallo), working with Doris Morgan and Frank Ruscetti, stimulated lymphocytes with phytohemagglutinin and found a growth factor in the culture fluid that allowed T cells to be maintained for more than nine months. They named it T-cell growth factor; it was later renamed interleukin-2.<sup>[1](https://irp.nih.gov/accomplishments/discovery-of-interleukin-2-il-2)</sup> The discovery and purification of IL-2 made long-term T-cell culture possible, which in turn enabled the discovery of human T-cell leukemia virus (HTLV), the first retrovirus identified in humans.<sup>[1](https://irp.nih.gov/accomplishments/discovery-of-interleukin-2-il-2)</sup>

## Receptor and signaling

IL-2 acts by binding the interleukin-2 receptor (IL-2R), a complex of up to three subunits: IL-2Rα (CD25), IL-2Rβ (CD122), and the gamma chain (CD132), the last shared with the receptors for IL-4, IL-7, IL-9, IL-15, and IL-21.<sup>[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7037245/)</sup> The βγ dimer binds IL-2 with intermediate affinity (K<sub>d</sub> ≈ 10<sup>−9</sup> M), while addition of the α chain creates the high-affinity trimeric receptor (K<sub>d</sub> ≈ 10<sup>−11</sup> M).<sup>[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7037245/)</sup><sup> • </sup><sup>[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC6472684/)</sup> Resting T cells express only the moderate-affinity βγ form and respond to very high IL-2 concentrations; activation induces α-chain expression, allowing responses to very low concentrations.<sup>[8](https://www.ncbi.nlm.nih.gov/books/NBK27118/)</sup>

Because IL-2Rα is not itself required for signaling, the distribution of CD25 across cell subsets determines which cells respond at a given IL-2 concentration. Treg cells express CD25 constitutively and at high levels, while effector CD4<sup>+</sup> T cells, CD8<sup>+</sup> T cells, and NK cells express only intermediate-affinity receptors unless activated.<sup>[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7037245/)</sup><sup> • </sup><sup>[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC10947368/)</sup> This difference underlies the dose-dependent biology: at low doses IL-2 preferentially supports Tregs, while high doses activate CD8<sup>+</sup> T cells and NK cells.<sup>[6](https://onlinelibrary.wiley.com/doi/full/10.1002/iid3.1165)</sup>

Signaling proceeds mainly through the JAK-STAT pathway, initiated by phosphorylation of JAK1 and JAK3 after receptor engagement, with secondary activation of the PI3K and MAPK pathways.<sup>[10](https://pubchem.ncbi.nlm.nih.gov/gene/IL2/human)</sup><sup> • </sup><sup>[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC10947368/)</sup> In T cells, STAT5-driven gene expression includes the receptor chains themselves, proliferation and survival proteins such as MYC and BCL-2, and the transcription factor FOXP3, the marker of Treg identity.<sup>[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7037245/)</sup>

## Physiologic role

Activated T cells synthesize IL-2 and its receptor together; antigen recognition with co-stimulation can increase IL-2 production as much as 100-fold, and the secreted cytokine then drives clonal expansion, with activated T cells dividing two to three times a day so that one cell can give rise to thousands of progeny bearing the same antigen receptor.<sup>[8](https://www.ncbi.nlm.nih.gov/books/NBK27118/)</sup> IL-2 also supports the differentiation and homeostasis of effector subsets including Th1, Th2, Th17, and memory CD8-positive T cells.<sup>[10](https://pubchem.ncbi.nlm.nih.gov/gene/IL2/human)</sup>

## High-dose therapy in cancer

The stimulatory effect of IL-2 on effector and NK cells motivated high-dose IL-2 treatment for cancer. Recombinant human IL-2 (aldesleukin) became the first FDA-approved immunotherapy for metastatic renal cell carcinoma (1992) and metastatic melanoma (1998).<sup>[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC10111960/)</sup> The approved regimen is 600,000 IU/kg (0.037 mg/kg) every 8 hours by 15-minute intravenous infusion, up to 14 doses per cycle and 28 doses per course, given in a hospital with intensive care support.<sup>[7](https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/103293s51%2C54lbl.pdf)</sup>

High-dose IL-2 produces severe, multisystem toxicity. The label carries a boxed warning for capillary leak syndrome, which can be life-threatening or fatal, along with neurologic toxicity and serious infections including sepsis and bacterial endocarditis.<sup>[7](https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/103293s51%2C54lbl.pdf)</sup> High doses saturate both high- and intermediate-affinity receptors and trigger massive release of proinflammatory cytokines as well as the capillary leak syndrome itself.<sup>[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC6509335/)</sup> The most common adverse reactions, each occurring in at least 30% of patients, include hypotension, hyperbilirubinemia, dyspnea, rash, diarrhea, oliguria, chills, vomiting, thrombocytopenia, nausea, confusional state, and increased creatinine.<sup>[7](https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/103293s51%2C54lbl.pdf)</sup>

**Durable responses in a minority.** Responses occur in a subset of patients and can be long-lasting. In the PROCLAIM registry of 362 patients treated between 2005 and 2012, metastatic melanoma patients had complete responses in 5% and partial responses in 10%, with median overall survival of 19.6 months; metastatic renal cell carcinoma patients had complete responses in 6% and partial responses in 9%, with median overall survival of 41 months. There were no treatment-related deaths among the 362 patients.<sup>[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC5099373/)</sup> A multicenter study of 100 patients who survived at least 5 years after high-dose IL-2 with no subsequent systemic therapy found progression-free survival ranging from 5+ to 30+ years, with 27 renal cell carcinoma and 32 melanoma patients alive at 10 or more years.<sup>[14](https://pmc.ncbi.nlm.nih.gov/articles/PMC8020079/)</sup> Randomized comparisons found that lower-dose regimens produced less toxicity but also lower response rates, and a systematic review concluded that non-high-dose IL-2 regimens should not be used as standard treatment for metastatic renal cell carcinoma.<sup>[15](https://pubmed.ncbi.nlm.nih.gov/18542758/)</sup>

## Low-dose therapy for autoimmune disease

The same dose dependence that limits cancer therapy creates an opposite use. Many autoimmune diseases involve insufficiency of regulatory T cells, and low-dose IL-2 selectively expands and activates Tregs because their constitutive high-affinity receptors outcompete other cells for the cytokine.<sup>[6](https://onlinelibrary.wiley.com/doi/full/10.1002/iid3.1165)</sup><sup> • </sup><sup>[16](https://www.sciencedirect.com/science/article/pii/S1568997226002016)</sup> In systemic lupus erythematosus, a disruption of Treg homeostasis caused by acquired IL-2 deficiency is considered a crucial event in pathogenesis.<sup>[6](https://onlinelibrary.wiley.com/doi/full/10.1002/iid3.1165)</sup>

Clinical evidence has accumulated mainly in lupus. A meta-analysis of eight trials found that after low-dose IL-2 treatment, 54.8% of SLE patients had distinct clinical remission, the SRI-4 response rate was 0.819 (95% CI 0.745–0.894), and SELENA-SLEDAI disease activity scores fell significantly (SMD = −2.109). Proportions of CD4<sup>+</sup> T and Treg cells increased, while CD8<sup>+</sup> T, Th1, Th2, and Th17 proportions did not change significantly. Injection site reactions and fever occurred in 33.1% and 14.4% of patients, and no serious adverse events were reported.<sup>[6](https://onlinelibrary.wiley.com/doi/full/10.1002/iid3.1165)</sup> A broader meta-analysis of 31 trials in autoimmune rheumatic diseases found significant increases in Tregs (SMD = 1.13) and Th17 cells (SMD = 0.50) after treatment, with disease activity scores including DAS28, SELENA-SLEDAI, and CDASI all significantly reduced.<sup>[17](https://pmc.ncbi.nlm.nih.gov/articles/PMC10796881/)</sup> A later meta-analysis of nine studies including 584 SLE patients treated with low-dose IL-2 found a mean SLEDAI reduction of −4.62 (95% CI −5.83, −3.40), alongside reduced anti-dsDNA antibody titers and increased complement C3, C4, and Treg counts, though controlled studies only partially achieved statistical significance.<sup>[16](https://www.sciencedirect.com/science/article/pii/S1568997226002016)</sup>

**Safety at low doses.** A meta-analysis of 24 randomized controlled trials covering 1,321 patients examined low-dose (<6 million IU/day) and ultra-low-dose (≤1 million IU/day) subcutaneous recombinant IL-2. Symptomatic venous thromboembolic events were not reported in any study arm (absolute risk difference 0%, 95% CI −0.1% to +0.1%), and ultra-low-dose regimens showed a negligible rate of severe adverse events.<sup>[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC6509335/)</sup> This contrasts with high-dose intravenous IL-2, which has been associated with acute thromboembolic events including venous thromboembolism and cardiac, cerebral, and hepatic venous thrombosis.<sup>[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC6509335/)</sup>

## Engineered IL-2 and current directions

The narrow therapeutic window of native IL-2 has driven extensive protein engineering. Approaches include IL-2 muteins with altered receptor affinity, PEG conjugation, fusion proteins, and cytokine-antibody complexes designed to bias activity toward either Tregs (for autoimmunity) or CD8<sup>+</sup> T cells and NK cells (for cancer) while sparing endothelial cells, which are implicated in capillary leak syndrome.<sup>[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC10947368/)</sup><sup> • </sup><sup>[18](https://www.nature.com/articles/s12276-024-01301-3)</sup> As of 2023, no engineered IL-2 compound had received regulatory approval for autoimmune or inflammatory disease, although nine next-generation IL-2-based compounds had entered phase I or II trials for indications including SLE, atopic dermatitis, psoriasis, ulcerative colitis, autoimmune hepatitis, rheumatoid arthritis, graft-versus-host disease, and type 1 diabetes.<sup>[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC10947368/)</sup> Early clinical data for engineered IL-2 therapies aimed at selectively stimulating effector cells in cancer have been disappointing, indicating that biased variant activity may differ between preclinical models and clinical experience.<sup>[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC10947368/)</sup>

IL-2 also remains a component of adoptive cell therapy. In tumor-infiltrating lymphocyte (TIL) treatment, IL-2 supports the infused cells, and trials have compared high-dose intravenous IL-2 (72,000 IU/kg every 8 hours, up to 15 doses) with low-dose subcutaneous IL-2 (2 million IU daily for 14 days), finding comparable overall toxicity with lower rates of grade 3 febrile neutropenia and shorter hospitalizations in the low-dose group.<sup>[19](https://jitc.bmj.com/content/14/4/e014378)</sup> Clinical trials continue across both cancer and autoimmune indications, including combinations of low-dose IL-2 with pembrolizumab and beta-only IL-2 variants.<sup>[20](https://www.cancer.gov/research/participate/clinical-trials/intervention/recombinant-interleukin-2)</sup>

## References

1. [Discovery of interleukin-2 (IL-2), NIH Intramural Research Program](https://irp.nih.gov/accomplishments/discovery-of-interleukin-2-il-2)
2. [Signaling and Function of Interleukin-2 in T Lymphocytes (Cantrell), University of Dundee repository](https://discovery.dundee.ac.uk/ws/portalfiles/portal/20704755/Signaling_and_Function_of_Interleukin_2_in_T_lymphocytes_Ross_Cantrell_2018.pdf)
3. [Landmarks, NCI Center for Cancer Research](https://ccr.cancer.gov/sites/default/files/landmarks_2017_web-508.pdf)
4. [Effects of interleukin-2 in immunostimulation and immunosuppression, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC7037245/)
5. [Signaling and Function of Interleukin-2 in T Lymphocytes, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC6472684/)
6. [Efficacy, safety and the lymphocyte subsets changes of low-dose IL-2 in patients with systemic lupus erythematosus: a systematic review and meta-analysis, Immunity, Inflammation and Disease (2024)](https://onlinelibrary.wiley.com/doi/full/10.1002/iid3.1165)
7. [PROLEUKIN (aldesleukin) prescribing information, FDA (2023)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/103293s51%2C54lbl.pdf)
8. [The production of armed effector T cells, Immunobiology, NCBI Bookshelf](https://www.ncbi.nlm.nih.gov/books/NBK27118/)
9. [Molecular engineering of interleukin-2 for enhanced therapeutic activity in autoimmune diseases, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC10947368/)
10. [IL2 (human), Gene Target, PubChem](https://pubchem.ncbi.nlm.nih.gov/gene/IL2/human)
11. [A systematic review of interleukin-2-based immunotherapies in clinical trials for cancer and autoimmune diseases, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC10111960/)
12. [Safety of low-dose subcutaneous recombinant interleukin-2: systematic review and meta-analysis of randomized controlled trials, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC6509335/)
13. [Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC5099373/)
14. [Long-term progression-free survival of patients with metastatic melanoma or renal cell carcinoma following high-dose interleukin-2, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC8020079/)
15. [Interleukin-2 in the treatment of unresectable or metastatic renal cell cancer: a systematic review and practice guideline, PubMed](https://pubmed.ncbi.nlm.nih.gov/18542758/)
16. [Low-dose interleukin-2 for the treatment of systemic lupus erythematosus: a systematic review and meta-analysis, ScienceDirect](https://www.sciencedirect.com/science/article/pii/S1568997226002016)
17. [Efficacy, Safety and the Lymphocyte Subset Changes of Low-Dose IL-2 in Patients with Autoimmune Rheumatic Diseases, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC10796881/)
18. [Harnessing IL-2 for immunotherapy against cancer and chronic infection, Experimental & Molecular Medicine](https://www.nature.com/articles/s12276-024-01301-3)
19. [HosTIL territory: mapping the landscape of toxicity in TIL therapy, Journal for ImmunoTherapy of Cancer](https://jitc.bmj.com/content/14/4/e014378)
20. [Clinical Trials Using Recombinant Interleukin-2, National Cancer Institute](https://www.cancer.gov/research/participate/clinical-trials/intervention/recombinant-interleukin-2)

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*Topic: Encyclopedia › Life and health › Biological foundations › Immunology and immune-system biology*

*Initially written Sep 17, 2026 · Reviewed: Sep 30, 2026; Oct 21, 2026 · Edited: Oct 15, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*

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License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license