Snell, Laura M.Xu, WenxiAbd-Rabbo, DialaBoukhaled, GiselleGuo, MengdiMacleod, Bethany L.Elsaesser, Heidi J.Hezaveh, KebriaAlsahafi, NirminLukhele, SabeloNejat, SaraPrabhakaran, RamanandanEpelman, SlavaMcGaha, Tracy L.Brooks, David G.2024-01-262024-01-262021Snell LM, Xu W, Abd-Rabbo D, et al. Dynamic CD4+ T cell heterogeneity defines subset-specific suppression and PD-L1-blockade-driven functional restoration in chronic infection. Nat Immunol. 2021;22(12):1524-1537. doi:10.1038/s41590-021-01060-7https://hdl.handle.net/1805/38214Inhibiting PD-1:PD-L1 signaling has transformed therapeutic immune restoration. CD4+ T cells sustain immunity in chronic infections and cancer, yet little is known about how PD-1 signaling modulates CD4+ helper T (TH) cell responses or the ability to restore CD4+ TH-mediated immunity by checkpoint blockade. We demonstrate that PD-1:PD-L1 specifically suppressed CD4+ TH1 cell amplification, prevents CD4+ TH1 cytokine production and abolishes CD4+ cytotoxic killing capacity during chronic infection in mice. Inhibiting PD-L1 rapidly restored these functions, while simultaneously amplifying and activating TH1-like T regulatory cells, demonstrating a system-wide CD4-TH1 recalibration. This effect coincided with decreased T cell antigen receptor signaling, and re-directed type I interferon (IFN) signaling networks towards dominant IFN-γ-mediated responses. Mechanistically, PD-L1 blockade specifically targeted defined populations with pre-established, but actively suppressed proliferative potential, with limited impact on minimally cycling TCF-1+ follicular helper T cells, despite high PD-1 expression. Thus, CD4+ T cells require unique differentiation and functional states to be targets of PD-L1-directed suppression and therapeutic restoration.en-USPublisher PolicyAdoptive transferB7-H1 antigenChronic diseaseLymphocytic choriomeningitisProgrammed cell death 1 receptorTh1 cellsArticle