Abstract
Abstract Viral infection and reactivation of latent viruses are major causes of mortality and morbidity following haematopoietic stem cell transplantation. Adoptive immunotherapy with CD8+ T cells has proven efficacy in preventing or treating post-transplant viral infection, including therapy with resting T cells that undergo homeostatic expansion in vivo that follows transplantation. However T cells continuously expanded in vitro in IL-2 lose many characteristics associated with efficacy in vivo, and most IL-2-expanded cells die soon after infusion. Here we describe an alternative expansion protocol for human CD8+ T cells that only exposes the cells briefly to IL-2. Survival of the cells after IL-2 withdrawal relies on the continuous presence of IL-7, and the cells eventually come to rest in the cultures. In this system, timed exposure of naïve CD8+ T cells to IL-12 and IL-21 generates memory cells with competent effector functions upon rechallenge, specifically strong production of IFNγ, TNFα and IL-2. The memory cells generated also have acquired a favourable phenotype associated with early differentiation status by both cell surface markers (CCR7, CD62L, CD27 and CD28) and transcription factors (eg Tcf-1). Although our system has been piloted on the expansion of naïve CD8+ T cells, we propose that this alternative protocol could be used to generate resting antigen-specific memory cells with improved efficacy in preventing or treating viral disease in immunocompromised patients.
Published Version
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