Checkpoint blockade promotes the clearance of persistent viral infections in IL-27Ra-deficient models 4836

Description T cell exhaustion, a hallmark of persistent viral infection and multiple cancers, is characterized by diminished effector function, aberrant cytokine production, and impaired memory response. Chronic viremia is perpetuated by immunoregulatory pathways, and while checkpoint blockade can partially restore T cell function, the mechanisms underlying this reversal remain to be studied. IL-27 is an essential immune regulator for CD8 T cell function. IL-27R deficiency leads to increased viral titers, reduced T cell function, and life-long viremia following LCMV Cl-13 infection. We demonstrated that B cell-derived IL-27 is crucial for resolving persistent viral infection. Given the severe and sustained immune-suppressed state of IL-27R deficient mice, we hypothesized that the blockade of known negative immune regulators could overcome exhaustion and promote viral clearance. To this end, we evaluated the ablation of IL-27R signaling combined with PD-1 blockade during persistent viral infection using Cl-13 infection. PD-1 inhibition in the absence of IL-27R signaling led to viral clearance during the persistent phase of infection without the immunopathology associated with early anti-PD-1 treatment. However, IFNAR blockade, previously shown to abrogate persistent viral infection, failed to clear persistent LCMV Cl-13 infection. Our findings highlight the role of checkpoint inhibition in rescuing immune control during severe exhausted states during chronic viral infections. Funding Sources NIH / AI164744 Topic Categories Viral Immunology (VIR)