Interleukin-35 regulates peripheral T cell activity in patients with Kawasaki disease

Interleukin-35 (IL-35) regulates immune cell function in inflammation, infection, cancer, and autoimmune diseases. However, the modulatory activity of IL-35 exerted on T cells is not fully understood in Kawasaki disease. For this purpose, the present study included 28 patients with Kawasaki disease and 16 healthy controls. The mRNA levels of IL-35 receptor subunits, including IL-12Rβ2 and gp130, were determined by conducting real-time PCR. CD4⁺ and CD8⁺ T cells were enriched, and stimulated with recombinant human IL-35. The influence of IL-35 on transcription factors and cytokine secretion by CD4⁺ T cells was assessed by performing real-time PCR and ELISA. The modulatory activity of IL-35 on CD8⁺ T cells was investigated by measuring target cell death, perforin/granzyme B secretion, and immune checkpoint molecule expression. IL-12Rβ2 and gp130 mRNA levels were comparable in CD4⁺ and CD8⁺ T cells between patients with Kawasaki disease and controls. Patients with Kawasaki disease showed stronger Th1, Th17, and Th22 responses, but weaker Treg response compared with controls. IL-35 stimulation suppressed Th1, Th17, and Th22 responses but enhanced Treg response. Patients with Kawasaki disease showed elevated CD8⁺ T cell-induced cytotoxicity. IL-35 stimulation inhibited CD8⁺ T cell-induced target cell death. The downregulation of IFN-γ expression and perforin/granzyme B secretion, and the upregulation of PD-1, CTLA-4, and LAG-3 expression following IL-35 stimulation were responsible for decreased CD8⁺ T cell-induced cytotoxicity. IL-35 may play a pivotal immunosuppressive role in T cell function, which may be involved in the protective mechanism against inflammation in Kawasaki disease.