All responses are triggered by sufficient antigen plus costimulatory signals (lightning bolt, row 1). Successful immune regeneration during acute infection and upon its resolution (row 2) illustrates the facultative (threat-dependent) nature of the progenitor and differentiated stages. Lifelong control of persistent low-level infection is analogous to perpetuation of autoimmune attack (row 3), with ongoing impetus for regeneration. Rows 4–6 depict vertical downward progression of tumor growth or increasing viral burden alongside hypothetical regenerative status without treatment (left) or with PD-1 blockade (right). The high incidence of immunotherapy resistance is probably related to progressive loss of self-renewing T cells as disease burden progresses. Optimal outcomes are more likely to be achieved when treatment is initiated earlier or with interventions that could prolong the window of self-renewing T cell abundance. Not shown is potential benefit of the arising of new neoantigens, which would appear as new red clones being deposited into the left-hand well. PD-1 blockade is depicted as lowering the activation energy and catalyzing greater division and differentiation from self-renewing cells while they persist. Adapted from ref. 134 with permission.