Graduate Student The Scripps Research Institute, California, United States
Disclosure(s):
Prajakta Warang: No financial relationships to disclose
Introduction/Rationale: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
