Novel mechanisms and new applications of low-dose IL-2 therapy

Interleukin 2 (IL-2) is emerging as a new therapy to induce immune tolerance to treat a broad range of autoimmune diseases. This project investigates how this new therapy influences infection and osteoporosis, two major comorbidities of autoimmune diseases. Glucocorticoid and conventional immunosuppressive therapies increase the risk of infection in patients with autoimmune diseases. In contrast, low-dose IL-2 therapy was found associated with reduced infection in patients with systemic lupus erythematosus (SLE). In line with the clinical observation, I examined low-dose IL-2 therapy in mice infected with influenza A virus and found it enhanced effector production of CD8+ T cells and accelerated viral clearance. Importantly, in mice with an acute infection of lymphocytic choriomeningitis virus (LCMV), low-dose IL-2 treatment exacerbated inflammation and organ damage and resulted in increased weight loss and mortality, which was largely driven by CD8+ T cells-mediated immunopathology promoted by IL-2 treatment. My lab previously revealed a novel CD8+ T cell subpopulation expressing CXCR5 and specializing in controlling chronic infections in B cell follicles, such as those in B cells and follicular helper T (TFH) cells. These cells, termed as follicular cytotoxic CD8+ T (TFC) cells, are tightly regulated by a transcriptional circuit composed of Bcl-6, Blimp1, TCF1, Id2 and Id3. In chronic LCMV infection in mice, I discovered that low-dose IL-2 administration reduced overall viral load but didn't benefit the viral control in follicles. Mechanistic studies further revealed that IL-2 suppressed the generation of TFC cells, which is predominately via a STAT5-Blimp-1 pathway. Last, I examined low-dose IL-2 therapy in ovariectomized (OVX)-induced mice model for osteoporosis and found low-dose IL-2 treatment significantly mitigated osteoporosis. The benefit of IL-2 therapy was beyond the reported function of IL-2 in the expansion of regulatory T (TREG) cells, which have been shown to reduce inflammation and inhibit the generation of osteoclasts (OCs). I discovered that IL-2 treatment not only directly suppressing osteoclastogenesis but also through an indirect mechanism by potentiating group 2 innate lymphoid (ILC2s) cells to produce inhibitory cytokines and surface interaction. Together, my study demonstrates that low-dose IL-2 therapy in autoimmune diseases adds additional benefits by reducing the risk of viral infection and mitigating osteoporosis. It also provides novel insights into the potential risk of low-dose IL-2 therapy in promoting CD8+ T cells-mediated immunopathology in severe systemic infection and not targeting specific viral reservoirs in B-cell follicles. This new knowledge will guide the clinical application of low-dose IL-2 therapy and help to design new therapeutic strategies for infection and osteoporosis