Regulatory T cells (Tregs) warrant immune homeostasis and sustained immune tolerance
Tregs are a subset of T lymphocytes. These are key immune cells that controls inflammation, immune responses against pathogens, and even immune responses against self-antigens. Regarding this last feature, it was showed in vivo that efficient Tregs ablation at any time in life in normal mice triggers multi-organs autoimmune reactions and extensive inflammation that are rapidly fatal. This means that the immune system is somehow “non perfect” and that immune cells (namely effector T cells, Teffs) would continuously attack and destroy our own tissues and organs in the absence of Tregs. In other words, Tregs participate to immune homeostasis and so-called self-tolerance.
Breakdown of immune tolerance resulting from Tregs/Teffs imbalance is the hallmark of autoimmune an inflammatory diseases (ADs)
ADs represent a wide class of pathologies mixing inflammation and autoimmunity. Multiple sclerosis, rheumatoid arthritis, systemic lupus erythematous, psoriasis, Crohn’s disease are amongst the most frequent ADs. ADs have this common root cause that they all present with a disruption of the immune balance between effector T cells (Teffs) and regulatory T cells (Tregs) leading to immune tolerance shortage. This means that Tregs cannot control the autoreactive attack of Teffs against self-antigens (normal tissues).
Interleukin-2 (IL2) is the cytokine indispensable for Tregs expansion/activation and survival
IL2 is a key cytokine that was originally described as permitting the activation and proliferation of T lymphocytes. It has been used clinically for the stimulation of effector immune response in certain cancers and infectious diseases, but with disappointing results. This has recently been explained by the discovery that IL2 is an essential cytokine for the survival and activation of Tregs. It has been observed that knocked-out mice for IL2 or its receptor are not immune deficient, but rather suffer from proliferative syndromes and ADs with phenotypes comparable to Tregs-depleted mice. This indicates that Teffs can develop and be functional in the absence of IL2, unlike Tregs. Consistently with the above paradigm, a deficit of IL2 or of its receptor has been reported in autoimmmune diseases including type-1 diabetes (T1D), multiple sclerosis (MS) and systemic lupus erythematosus (SLE).
Selective activation of Tregs with low dose IL2 is supported by a well-characterized mechanism of action
The dual role of IL2 has been very well explained on molecular bases. IL2 molecule binds to 3 different subunits of the same receptor (IL2-Rα, IL2-Rβ and IL2-Rγ). The transduction of the signal occurs through IL2-Rβ and IL2-Rγ while IL2-Rα is the binding subunit. Tregs and Teffs constitutively express both IL2-Rβ and IL2-Rγ while only Tregs constitutively express the “high affinity” receptor subunit IL2-Rα. This structural difference is responsible for Tregs preferential uptake of IL2 as compared to Teffs.
Low dose IL2 allows reinstating a proper Tregs/Teffs balance and thus represents an unprecedented therapeutic approach for treating patients with autoimmune and inflammatory diseases.
Main scientific publications
- Grinberg-Bleyer, Y., Baeyens, A., You, S., Elhage, R., Fourcade, G., Gregoire, S., Cagnard, N., Carpentier, W., Tang, Q., Bluestone, J., et al. (2010). IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J. Exp. Med. 207, 1871–1878.
- Saadoun D, Rosenzwajg M, Joly F, Six A, Carrat F, Thibault V, Sene D, Cacoub P, Klatzmann D. (2011). Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med ;365(22):2067-77.
- Hartemann A., Bensimon G., Payan C., Jacqueminet S., Bourron O., Nicolas N., Fonfrede M., Rosenzwajg M., Bernard C., Klatzmann D. (2013). Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 1: 295–305.
- Klatzmann, D., and Abbas, A.K. (2015). The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat. Rev. Immunol. 15, 283–294.
- Beers DR, Zhao W, Wang J, Zhang X, Wen S, Neal D, Thonhoff JR, Alsuliman AS, Shpall EJ, Rezvani K,
Appel SH (2017). ALS patients’ regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity. JCI Insight 2(5):e89530. - Rosenzwajg M, Lorenzon R, Cacoub P, et al. (2019). Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial. Annals of the Rheumatic Diseases 78:209-217.
- Camu W, Mickunas M, Veyrune JL, Payan C, Garlanda C, Locati M, Juntas-Morales R, Pageot N, Malaspina A, Andreasson U, Kirby J, Suehs C, Saker S, Masseguin C, De Vos J, Zetterberg H, Shaw PJ, Al-Chalabi A, Leigh PN, Tree T, Bensimon G (2020). Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial. EBioMedicine;59:102844.
- Rosenzwajg, M., Salet, R., Lorenzon, R. et al. (2020). Low-dose IL-2 in children with recently diagnosed type 1 diabetes: a Phase I/II randomised, double-blind, placebo-controlled, dose-finding study. Diabetologia 63, 1808–1821.
- Humrich JY, Cacoub P, Rosenzwajg M, Pitoiset F, Pham HP, Guidoux J, Leroux D, Vazquez T, Riemekasten G, Smolen JS, Tsokos G, Klatzmann D. Low-dose interleukin-2 therapy in active systemic lupus erythematosus (LUPIL-2): a multicentre, double-blind, randomised and placebo-controlled phase II trial. Ann Rheum Dis. 2022 Aug 16:annrheumdis-2022-222501