IL-2 Protects Lupus-Prone Mice from Multiple End-Organ Damage by Limiting CD4−CD8− IL-17–Producing T Cells

Abstract

Interleukin-2 (IL-2), a cytokine with pleiotropic effects, is critical for immune cell activation and peripheral tolerance. Although the therapeutic potential of IL-2 has been previously suggested in autoimmune diseases, the mechanisms whereby IL-2 mitigates autoimmunity and prevents organ damage remains unclear. Using an inducible recombinant adeno-associated virus (rAAV) vector we investigated the effect of low systemic levels of IL-2 in lupus-prone MRL/Faslpr/lpr (MRL/lpr) mice. Treatment of mice after the onset of disease with IL-2-rAAV resulted in reduced mononuclear cell infiltration and pathology of various tissues including skin, lungs and kidneys. In parallel, we noted a significant decrease of IL-17-producing CD3+CD4−CD8− double-negative T cells and an increase in CD4+CD25+Foxp3+ immunoregulatory T cells (Treg) in the periphery. We also show that IL-2 can drive DN T cell death through an indirect mechanism. Notably, targeted delivery of IL-2 to CD122+ cytotoxic lymphocytes effectively reduced the number of DN T cells and lymphadenopathy whereas selective expansion of Treg by IL-2 had no effect on DN T cells. Collectively, our data suggest that administration of IL-2 to lupus-prone mice protects against end-organ damage and suppresses inflammation by dually limiting IL-17-producing DN T cells and expanding Treg.

Rapid induction of clinical remission by low-dose interleukin-2 in a patient with refractory SLE

“…In line with this, two independent clinical studies showed recently that low-dose IL-2 induced expansion of the Treg pool and reduced clinical symptoms in two different immunological diseases without known IL-2 deficiency 4 5. These promising clinical findings in conjunction with preclinical data3 6 7 provide strong rationales for an IL-2-based immunotherapy of SLE in order to restore Treg activity and, thus, to re-establish endogenous mechanisms of tolerance that can counteract autoimmunity.…”

Engagement of SLAMF3 enhances CD4 + T-cell sensitivity to IL-2 and favors regulatory T-cell polarization in systemic lupus erythematosus

“…An impaired IL-2 level is associated with a reduced suppressive function of Tregs (4,12,16,25). Moreover, IL-2 plays a role in mounting adequate cytotoxic responses.…”

“…Most reports on human SLE have shown abnormal numbers/function of Tregs in the periphery (18)(19)(20)(21)(22). Replenishment of IL-2 in lupus-prone mice and in human SLE patients ameliorates disease manifestations through the expansion of Tregs (16,(23)(24)(25)(26)(27).…”

T cells and IL-17 in lupus nephritis

“…In addition, it has been reported that the aberrant functions of NF-κB and activator protein 1 (AP1) in SLE T cells contribute to decreased IL2 transcription [29, 30]. More recently, our lab has reported that administration of low dose IL-2 by using an inducible recombinant adeno-associated virus vector to lupus-prone mice results in increased Treg cell numbers and function, suppressed IL-17 production and tissue damage of kidneys [31]. Taken together, limited IL-2 levels skew the balance between Tregs and Th17 in favor of the latter (Figure 1).…”