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Dynamic Differentiation of Activated Human Peripheral Blood CD8⁺ and CD4⁺ Effector Memory T Cells

Department of Cellular Immunology, German Cancer Research Center, Heidelberg, Germany

Two functionally different memory T cell subsets were originally defined based on their different CCR7 expression profile, but the lineage relationship between these subsets referred to as central memory T cells (T_CM) and effector memory T cells (T_EM), is not resolved. A prevalent model proposes a linear progressive differentiation from T_CM to T_EM. Our results demonstrate that on activation, human CCR7^–CD62L^– peripheral blood CD8⁺ and CD4⁺ T_EM cells exhibit a dynamic differentiation, involving transient as well as stable changes to T_CM phenotype and properties. Whereas the larger fraction of T_EM cells increases expression of effector molecules, such as perforin or IFN-, a smaller fraction first acquires CCR7 expression. We demonstrate that this acquisition of lymph node homing potential is associated with strong proliferation similar to that of activated T_CM cells. After proliferation, most of these cells lose CCR7 expression again and acquire effector functions (e.g., perforin production). A small proportion (6%), however, maintain phenotypic and functional T_CM properties over a long time interval. These results suggest that T_EM cells provide immediate effector function by a fraction of cells as well as self-renewal by others through up-regulation of CCR7 followed by either secondary peripheral effector function or long term maintenance of T_CM-like properties.

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