Immune checkpoint blockade enhances CD4 effector function and enables control of persistent viral infection 2310195

Abstract

Abstract Introduction 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. Although immune checkpoint blockade (ICB) therapies, such as PD-1 inhibition, can transiently reinvigorate exhausted CD8+ T cell subsets, their efficacy is limited by the small pool of self-renewing, progenitor-like TCF1+ CXCR5+ CD8+ T cells. We previously demonstrated that B cell—derived IL-27 signaling is required for the expansion of this progenitor-like population during chronic infection. Using an IL-27 receptor—deficient mouse model, we uncover a previously unrecognized mechanism by which PD-1 inhibition mediates viral clearance and enhanced humoral responses. Methods IL-27 receptor—deficient mice were infected with LCMV clone 13 and treated with PD-1—blocking antibodies at later stages post-infection. Following completion of antibody treatment, immune responses were analyzed using flow cytometry to characterize T cell and B cell subsets. Antiviral antibody responses and viral clearance were evaluated using serological assays, sequencing approaches, and focus-forming assay. Results PD-1 inhibition promoted viral clearance during the persistent phase without inducing the immunopathology typically observed with early anti—PD-1 treatment. This was associated with increased IL-21 production by T follicular helper (Tfh) cells, leading to augmented cytotoxic and humoral antiviral responses. Conclusion Our findings reveal a previously unrecognized and novel, IL-27—independent CD4+ T cell axis through which PD-1 checkpoint blockade restores antiviral immunity during persistent viral infection. These results redefine the mechanistic landscape of checkpoint immunotherapy, highlighting CD4+ T cells as critical effectors in controlling persistent viral infections. Funding Source N/A Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)