Effector differentiation is not prerequisite for generation of memory cytotoxic T lymphocytes

The lineage relationship between short-lived effector T cells and long-live d memory cells is not fully understood. We have described T-GFP mice previo usly, in which naive and early activated T cells express GFP uniformly, whe reas cells that have differentiated into effector cytotoxic T cells selecti vely lose GFP expression. Here we studied antigen-specific CD8 T cell diffe rentiation using T GFP mice crossed to the TCR transgenic (Tg) mice P14 (sp ecific for the lymphocytic choriomeningitis virus glycoprotein peptide, gp3 3-41). After activation with antigenic peptide, P14XT-GFP CD8(+) T cells cu ltured in high-dose IL-2 developed into cells with effector phenotype and f unction: they were blastoid, lost GFP expression, expressed high levels of activation and effector markers, and were capable of immediate cytotoxic fu nction. In contrast, cells cultured in IL-15 or low-dose IL-2 never develop ed into full-fledged effector cells. Rather, they resembled memory cells: t hey were smaller, were GFP(+), did not express effector markers, and were i ncapable of immediate cytotoxicity. However, they mediated rapid-recall res ponses in vitro. After adoptive transfer, they survived in vivo for at leas t 10 weeks and mounted a secondary immune response after antigen rechalleng e that was as potent as endogenously generated memory cells. In addition to providing a simple means to generate memory cells in virtually unlimited n umbers, our results suggest that effector differentiation is not a prerequi site for memory cell generation.