Protective immunity against pathogens depends on the efficient generation of functionally diverse effector and memory T lymphocytes. However, whether plasticity during effector-to-memory CD8+ T cell differentiation affects memory lineage specification and functional versatility remains unclear. Using genetic fate mapping analysis of highly cytotoxic KLRG1+ effector CD8+ T cells, we demonstrated that KLRG1+ cells receiving intermediate amounts of activating and inflammatory signals downregulated KLRG1 during the contraction phase in aBach2-dependent manner and differentiated into all memory T cell linages, including CX3CR1int peripheral memory cells and tissue-resident memory cells. “ExKLRG1” memory cells retained high cytotoxic and proliferative capacity distinct from other populations, which contributed to effective anti-influenza and anti-tumor immunity. Our work demonstrates that developmental plasticity of KLRG1+ effector CD8+ T cells is important in promoting functionally versatile memory cells and long-term protective immunity.In Brief
Herndler-Brandstetter et al. demonstrate that KLRG1+IL-7Rα+ effector CD8+ T cells downregulate KLRG1 in a Bach2-dependent manner and differentiate into long-lived circulating and tissue-resident “exKLRG1” memory cells. Developmental plasticity of KLRG1+ effector cells therefore drives functional diversity within memory T cell lineages and promotes enhanced anti-influenza and anti-tumor immunity.