Browsing by Author "Prabhakaran, Ramanandan"

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    Dynamic CD4+ T cell heterogeneity defines subset-specific suppression and PD-L1-blockade-driven functional restoration in chronic infection
    (Springer Nature, 2021) Snell, Laura M.; Xu, Wenxi; Abd-Rabbo, Diala; Boukhaled, Giselle; Guo, Mengdi; Macleod, Bethany L.; Elsaesser, Heidi J.; Hezaveh, Kebria; Alsahafi, Nirmin; Lukhele, Sabelo; Nejat, Sara; Prabhakaran, Ramanandan; Epelman, Slava; McGaha, Tracy L.; Brooks, David G.; Microbiology and Immunology, School of Medicine
    Inhibiting 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.