Interleukin-37 Enhances the Suppressive Activity of Naturally Occurring CD4⁺CD25⁺ Regulatory T Cells

Naturally occurring CD4⁺CD25⁺ regulatory T cells (Tregs) are essential for the suppression of autoimmunity and can control the immune-mediated pathology during the early phase of sepsis. Our previous data showed that silencing interleukin-37 (IL-37) in human CD4⁺CD25⁺ Tregs obviously reduced the suppressive activity of CD4⁺CD25⁺ Tregs. Here, we found that rhIL-37 stimulation markedly enhanced the suppressive activity of CD4⁺CD25⁺ Tregs isolated from naive C57BL/6 J mice in the absence or presence of lipopolysaccharide (LPS). Treatment with rhIL-37 could significantly upregulate the expression of cytotoxic T-lymphocyte-associated antigen (CTLA)-4 and forkhead/winged helix transcription factor p3 (Foxp3) on CD4⁺CD25⁺ Tregs. Also, rhIL-37 stimulation promoted the production of transforming growth factor-β1 (TGF-β1) but not IL-10 in the supernatants of cultured CD4⁺CD25⁺ Tregs. Pretreated CD4⁺CD25⁺ Tregs with rhIL-37 in the presence or absence of LPS were cocultured with CD4⁺CD25^- T cells, ratio of IL-4/interferon-γ in the supernatants obviously increased in IL-37-stimulated groups. In addition, early administration of IL-37 significantly improved the survival rate of septic mice induced by cecal ligation and puncture. Taken together, we concluded that rhIL-37 enhances the suppressive activity of CD4⁺CD25⁺ Tregs and might be a potential immunomodulator for the treatment of septic complications.