Engraftment of human central memory-derived effector CD8+ T cells in immunodeficient mice

Abstract

In clinical trials of adoptive T-cell therapy, the persistence of transferred cells correlates with therapeutic efficacy. However, properties of human T cells that enable their persistence in vivo are poorly understood, and model systems that enable investigation of the fate of human effector T cells (T(E)) have not been described. Here, we analyzed the engraftment of adoptively transferred human cytomegalovirus pp65-specific CD8(+) T(E) cells derived from purified CD45RO(+)CD62L(+) central memory (T(CM)) or CD45RO(+)CD62L(-) effector memory (T(EM)) precursors in an immunodeficient mouse model. The engraftment of T(CM)-derived effector cells (T(CM/E)) was dependent on human interleukin-15, and superior in magnitude and duration to T(EM)-derived effector cells (T(EM/E)). T-cell receptor Vβ analysis of persisting cells demonstrated that CD8(+) T(CM/E) engraftment was polyclonal, suggesting that the ability to engraft is a general feature of T(CM/E.) CD8(+) T(EM/E) proliferated extensively after transfer but underwent rapid apoptosis. In contrast, T(CM/E) were less prone to apoptosis and established a persistent reservoir of functional T cells in vivo characterized by higher CD28 expression. These studies predict that human CD8(+) effector T cells derived from T(CM) precursors may be preferred for adoptive therapy based on superior engraftment fitness.