Dynamic CD4(+) T cell heterogeneity defines subset-specific suppression and PD-L1-blockade-driven functional restoration in chronic infection

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 (T-H) cell responses or the ability to restore CD4(+) T-H-mediated immunity by checkpoint blockade. We demonstrate that PD-1:PD-L1 specifically suppressed CD4(+) T(H)1 cell amplification, prevents CD4(+) T(H)1 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 T(H)1-like T regulatory cells, demonstrating a system-wide CD4-T(H)1 recalibration. This effect coincided with decreased T cell antigen receptor signaling, and re-directed type I interferon (IFN) signaling networks towards dominant IFN-gamma-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. Snell et al. examine the heterogeneity of CD4(+) T cells in chronic viral infection, showing that PD-L1 blockade enhances a cytotoxic gene program in antigen-specific T(H)1 cells and can restore antiviral CD4(+) T cell killer function.

Automated summary

Inhibiting PD-1:PD-L1 signaling can restore the immune function of CD4(+) T cells in chronic infections and modulate the activation of T regulatory cells. This study demonstrates the heterogeneity of CD4(+) T cells in chronic viral infection and shows that PD-L1 blockade can enhance cytotoxic gene programs in antigen-specific T(H)1 cells.