Immune checkpoint blockade enhances CD4 effector function to control persistent viral infection 2267612
T cell exhaustion, a defining hallmark of chronic viral infections and cancer, is characterized by the progressive loss of effector function and sustained expression of inhibitory receptors on T cells. Although immune checkpoint blockade (ICB) therapies, such as PD-1 inhibition, can transiently reinvigorate subsets of exhausted CD8+ T cells, their efficacy remains constrained by the limited pool of self-renewing, progenitor-like TCF1+ CXCR5+ CD8+ T cells. We have previously demonstrated that B cell—derived IL-27 signaling is necessary for the expansion and maintenance of this progenitor-like population during chronic infection. Using an IL-27 receptor deficient mouse model, we reveal a previously unrecognized mechanism by which PD-1 blockade mediates viral clearance. We demonstrate that PD-1 inhibition enhances CD4+ T cell function, specifically through increased IL-21 production from T follicular helper (Tfh) cells which promotes both humoral and cytotoxic antiviral responses. Our findings identify a novel IL-27 independent CD4+ T cell axis through which checkpoint blockade controls persistent viremia. To determine the impact of checkpoint inhibition on persistent viral infection, IL-27 receptor—deficient mice were infected with chronic lymphocytic choriomeningitis virus (LCMV clone 13) and treated with PD-1 blocking antibodies. We used flow cytometry and viral titers to evaluate CD4+ and CD8+ T cell subsets, the importance of IL-21, and persistent viral clearance. PD-1 blockade restored antiviral immunity in IL-27 receptor—deficient mice and resulted in enhanced CD4+ T cell function. We saw increased IL-21 production from T follicular helper cells that led to higher cytotoxic and humoral antiviral responses. Our studies reveal that PD-1 blockade can drive persistent viral clearance through an IL-27—independent mechanism that involves IL-21—producing CD4+ T cells. N/A Viral Immunology (VIR)