Muhammad Ausaf Ehsan

Background: Systemic lupus erythematosus is a chronic autoimmune disease driven by loss of immune tolerance, autoreactive lymphocyte activation, autoantibody production, and immune-complex mediated organ injury. Regulatory T cells normally suppress autoreactive immune responses, but Treg number and function are impaired in SLE, partly because patients have insufficient interleukin-2 signaling.¹ Because Tregs express high levels of CD25, the high-affinity IL-2 receptor alpha chain, they are especially sensitive to low concentrations of IL-2.² Current SLE therapies can control inflammation, but many broadly suppress immunity rather than correcting the underlying tolerance defect, leaving a need for more targeted immune-restoring approaches. This creates a therapeutic opportunity: rather than broadly suppressing immunity with conventional treatments, low-dose IL-2 may selectively restore Treg-mediated immune tolerance while limiting pathogenic effector T-cell activation.^1,2

Objective: This narrative review evaluated whether IL-2 deficiency contributes to Treg dysfunction in SLE and whether low-dose IL-2 therapy can restore immune homeostasis through selective Treg expansion.

Search Methods: A PubMed literature search was conducted for articles published from 2017 to 2023 using MeSH terms and keywords including “systemic lupus erythematosus,” “low-dose interleukin-2,” “regulatory T cells,” “FOXP3,” “STAT5,” “T follicular helper cells,” “autoimmunity,” and “lupus nephritis.” Primary mechanistic, preclinical, translational, and clinical studies most relevant to IL-2 signaling, Treg biology, and SLE treatment were reviewed.

Results: Mechanistic studies show that even low-threshold IL-2 receptor signaling is required for Treg development, survival, suppressive capacity, and maintenance of FOXP3 expression.⁴ IL-2 signaling activates the JAK-STAT pathway, and STAT5 directly supports FOXP3 transcriptional programs that preserve Treg identity and function.⁵ In lupus-prone mice, impaired IL-2 signaling reduces Treg populations while expanding T follicular helper cells, promoting germinal-center responses, autoantibody production, and lupus nephritis. IL-2 supplementation reversed these changes by expanding Tregs, reducing T follicular helper cell activity, decreasing germinal-center B-cell responses, and improving renal pathology.³ Translational and clinical studies further support this mechanism. Low-dose IL-2 preferentially induced STAT5 phosphorylation in Tregs and expanded stable FOXP3-positive Treg populations with limited activation of conventional effector T cells.² In a phase I/IIa clinical trial of patients with refractory SLE, low-dose IL-2 selectively expanded CD4-positive CD25-positive FOXP3-positive Tregs, improved the Treg-to-effector T-cell balance, and was associated with reduced disease activity in a subset of patients with minimal serious toxicity.¹ Together, these findings connect molecular Treg stabilization with measurable preclinical and early clinical improvement.

Conclusion: IL-2 deficiency is a central contributor to immune dysregulation in SLE because it weakens the Treg “off switch” needed to restrain autoreactive T- and B-cell responses. Current evidence suggests that low-dose IL-2 can restore immune balance by activating the IL-2-STAT5-FOXP3 axis and selectively expanding functional Tregs. Although early clinical findings are promising, larger placebo-controlled trials are needed to define optimal dosing, durability of response, long-term safety, and whether low-dose IL-2 can be integrated with existing SLE therapies or future Treg-based strategies.

Works Cited:

1. Humrich JY, von Spee-Mayer C, Siegert E, et al. Low-dose interleukin-2 therapy in refractory systemic lupus erythematosus: a phase I/IIa clinical trial. Ann Rheum Dis. 2019;78(2):181-185. doi:10.1136/annrheumdis-2018-214036
2. Rosenzwajg M, Lorenzon R, Cacoub P, et al. Low-dose interleukin-2 fosters a dose-dependent regulatory T cell tuned milieu in autoimmune diseases including systemic lupus erythematosus. Sci Transl Med.2019;11(489):eaaw7202. doi:10.1126/scitranslmed.aaw7202
3. Mizui M, Koga T, Lieberman LA, et al. IL-2 protects lupus mice from autoimmune disease by expanding regulatory T cells and inhibiting follicular helper T cells. J Immunol. 2018;200(6):1838-1847. doi:10.4049/jimmunol.1701510
4. Yu A, Zhu L, Altman NH, Malek TR. A low interleukin-2 receptor signaling threshold supports the development and homeostasis of T regulatory cells. Immunity. 2019;51(4):648-663.e6. doi:10.1016/j.immuni.2019.09.012
5. Raeber ME, Rosalia RA, Schmid D, Karakus U, Boyman O. Interleukin-2 signals converge in FOXP3 to program regulatory T cell function. Nat Immunol. 2020;21:1441-1453. doi:10.1038/s41590-020-0789-3