Dynamic CD4 T cell heterogeneity defines subset-specific suppression and PDL1-blockade driven functional restoration in chronic infection [Bulk-seq]

Inhibiting PD1:PDL1 signaling has transformed therapeutic immune restoration. CD4 T cells are critical to sustain immunity in chronic infections and cancer, yet little is known about how PD1/L1 modulates CD4 T helper (Th) responses or the ability to restore CD4 Th-mediated immunity by inhibiting PD1/L1 signaling. We demonstrate that PD1/L1 specifically suppresses CD4 Th1 cell amplification, prevents CD4 Th1 cytokine production, and abolishes CD4 CTL killing capacity during chronic infection. Inhibiting PDL1 during chronic infection rapidly restored these functions, while simultaneously enhancing Th1-like Treg amplification and activation, indicating a system-wide CD4-Th1 recalibration. Paradoxically, PDL1-blockade decreased TCR signaling, while re-directing intrinsically-suppressive type I interferon networks towards dominant IFN?-mediated responses. Mechanistically, PDL1-blockade specifically targeted defined populations with pre-established, but actively-suppressed proliferative potential, with limited impact on minimally-cycling TCF1+ Tfh, despite high PD1 expression. Thus, CD4 T cells require unique differentiation and functional states to be targets of PDL1-directed suppression and therapeutic restoration. Overall design: RNA-seq on Th1 and Tfh virus-specific CD4 SMARTA T cells at Day 7 LCMV-Armstrong