Granzyme A-expressing Terminal Effector T Cells Dedifferentiate into Long-lived Memory T Cells

Memory T cells are critical for vaccines and T-cell-based therapies. However, the differentiation path of memory T cells is not completely understood. Early bulk cell population-based studies support a linear model, in which effector T cells lose the effector program and dedifferentiate into memory T cells. Recent research supports a bifurcation model, where T cells choose one of the two paths, either the effector or the memory path, at an early stage of T cell responses. Terminal effector T cells lose the capacity to become memory T cells. Here, we first demonstrate that the expression of granzyme A is largely distinct from that of granzyme B and marks terminal cytotoxic effector CD8⁺ T cells with reduced polyfunctionality. Using a granzyme A-fate mapping mouse line and an acute viral infection model, we discovered that early memory T cells are largely derived from cells lacking a history of granzyme A expression, supporting the bifurcation model. Progressively, granzyme A-expressing terminal effector T cells dedifferentiate into functional long-term memory T cells. At the late memory phase, memory T cells are a mixed population composed of cells with different differentiation paths (i.e., the linear and the bifurcated paths) that coordinate to provide balanced immune protection.