Interleukin-35 (IL-35) has an immunosuppressive function through the regulation of immune cells during infectious diseases, autoimmune disorders, and cancers. The modulatory role of IL-35 in T lymphocytes, which are involved in host immune responses during human immunodeficiency virus-1 (HIV-1) infection, has not been elucidated. The aim of the current study was to investigate the role of regulatory function of IL-35 to T-cell activity in patients living with chronic HIV-1 infection. Sixty-seven patients living with chronic HIV-1 infection and 17 controls were enrolled in the study. IL-35 levels were measured via an enzyme-linked immunosorbent assay. Purified CD4⁺ and CD8⁺ T cells were stimulated with recombinant human IL-35. The secretion of cytokines and cytotoxic molecules, the mRNA levels of IL-35 receptor subunits and transcription factors, the expression of immune checkpoint molecules, and cell proliferation were assessed to evaluate the effect of IL-35 on T lymphocyte function in vitro. Compared with controls, patients living with chronic HIV-1 infection presented increased plasma IL-35 levels. IL-35 stimulation did not affect either the expression of IL-35 receptor subunits or the proliferation of CD4⁺ and CD8⁺ T cells from either patients living with chronic HIV-1 infection or controls. IL-35 stimulation downregulated transcription factor mRNA expression and cytokine secretion by CD4⁺ T cells as well as cytotoxic molecule production by CD8⁺ T cells from both patients living with chronic HIV-1 infection and controls. This process was accompanied by increased expression of immune checkpoint molecules on CD4⁺ and CD8⁺ T cells. The addition of IL-35 also reduced perforin and granzyme B secretion by HIV-1-specific CD8⁺ T cells from patients living with chronic HIV-1 infection. Increased plasma IL-35 in patients living with chronic HIV-1 infection might dampen the activation of CD4⁺ and CD8⁺ T cells, leading to T-cell exhaustion.

Keywords: T lymphocytes; human immunodeficiency virus-1; immune exhaustion; interleukin-35.