T Cell Exhaustion: Chronic Stimulation and the Exhaustion Hierarchy

When CD8⁺ T cells face antigen that never clears — a chronic viral infection or a persistent tumor — they don't stay effective forever. Continuous receptor signaling drives them down a well-characterized path called exhaustion: inhibitory receptors like PD-1, LAG-3, TIM-3 and TIGIT accumulate, and effector functions shut off one by one in a fixed order (IL-2, then TNF-α, then IFN-γ, then cytotoxicity last). This simulation renders that trajectory in 3D — a population of T cells surrounding a tumor mass, each cell's color and receptor load reflecting its own accumulated exhaustion score — and lets you test the central clinical question behind checkpoint-inhibitor immunotherapy: does blocking PD-1 still work? The model enforces a biologically real answer — reinvigoration only happens for progenitor-exhausted cells that haven't crossed the epigenetic fixation point; cells that have gone terminal stay locked out no matter the dose.