An early protective effect of IL-9 in murine systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a progressive antibody-mediated autoimmune disease characterized by systemic immune complex deposition. A subset of SLE patients has elevated CD4+IL-9+ T cells as well as increased levels of secreted interleukin (IL)-9 and IL9 messenger RNA compared with healthy control subjects. However, because IL-9 can have both pro- and anti-inflammatory effects in autoimmune disease, its function in SLE is unclear. We use the MRL/lpr murine model of SLE to demonstrate that IL-9 exhibits protective activity in the early stages of disease. Treatment of these mice with an IL-9 neutralizing antibody from 6 to 12 wk of age results in an expansion of immune cells, leading to exacerbation of disease. In contrast, treatment with anti-IL-9 from 6 to 18 wk of age does not significantly alter disease course compared with isotype control. Anti-IL-9 antibody treatment of these mice results in reduced systemic IL-2 levels, IL-9+ type 2 innate lymphoid cells, and regulatory T cells in the kidney, suggesting an IL-9-dependent suppressive cellular circuit similar to that observed in rheumatoid arthritis. Importantly, supplementation of IL-2 during IL-9 blockade recovers regulatory T cell numbers and limits disease. Together, these data demonstrate an IL-9-dependent suppressive circuit that is evident early in the development of SLE which may be amenable to manipulation to achieve a therapeutic benefit.