Figure 4. Proposed mechanism of PD-1-directed immunotherapy during chronic viral infection and cancer. (A) After the establishment of T-cell exhaustion, PD-1/PD-L1 axis plays a role in 2 different ways. First, PD-1/PD-L1 interaction inhibits the proliferation and differentiation of stem cell-like CD8 T cells into the more differentiated CD8 T-cell subsets. CD28 is a major target for PD-1-mediated suppression. Next, PD-L1 on infected cells or tumor cells impairs the cytolytic function and cytokine production of PD-1⁺ Ag-specific differentiated CD8 T-cell subsets. (B) In the absence of PD-1-mediagted signals, the proliferation and differentiation of stem cell-like CD8 T cells into transitory and terminally differentiated CD8 T cells are accelerated and this happens in a CD28/B7-dependent manner. The increased population of transitory subset showing the highest anti-viral/tumor activity is critical for the viral clearance and tumor regression. In terms of the quality, the cytolytic function and cytokine production of transitory and terminally differentiated CD8 T-cell subsets might be increased after PD-1 blockade.