A human memory T cell subset with stem cell–like properties

Abstract

Immunological memory is thought to depend upon a stem cell-like, self-renewing population of lymphocytes capable of differentiating into effector cells in response to antigen re-exposure. Here we describe a long-lived human memory T-cell population that displays enhanced self-renewal and multipotent capacity to derive central memory, effector memory and effector T cells. These cells, specific for multiple viral and self-tumor antigens, were found within a CD45RO−, CCR7+, CD45RA+, CD62L+, CD27+, CD28+ and IL-7Rα+ T-cell compartment characteristic of naïve T cells. However, they expressed increased levels of CD95, IL-2Rβ, CXCR3, and LFA-1, and exhibited numerous functional attributes distinctive of memory cells. Compared to known memory populations, these lymphocytes displayed increased proliferative capacity, more efficiently reconstituted immunodeficient hosts and mediated superior anti-tumor responses in a humanized mouse model. The identification of a human stem cell-like memory T-cell population is of direct relevance to the design of vaccines and T-cell therapies.

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy

“…Improved clinical efficacy of adoptive T cell therapy could be reached by generating tumor-specific T cell products with an early differentiation state, as they show superior longevity and proliferative capacity. 1-3,5-9,15-21,24,25,29-35 This could be accomplished by inhibition of the AKT pathway, as was previously shown by us and others. 15-21 In this study, we aimed to further optimize AKT-inhibited CD8 + T cells by exploring AKT-inhibitors with diverse modality of action, and further characterize these cells for their phenotype, transcriptome, metabolism and functionality.…”

“…To determine whether both allosteric and ATP-competitive AKT-inhibitors show similarities with any of the natural T cell subsets, a principal component analysis was performed. This was based on a set of 900 transcripts which are differentially expressed in the T cell subsets T N , T SCM , T CM and effector memory T cells (T EM ) as previously described by Gattinoni et al 24 This analysis revealed that despite their unique transcriptome profiles, both allosteric AKT-inhibitors (left panel) as well as ATP-competitive AKT-inhibitors (right panel) resembled the naturally occurring T SCM subset (Figure 3B). In contrast, DMSO-treated control T cells clustered more closely with the natural occurring T EM cells.…”

“…Importantly, both IL7Rα and co-stimulatory receptor CD28 were higher in all Akt-inhibited conditions (Figure 2C). Moreover, as superior proliferative capacity is one of the major advantages of early memory CD8 + T cells, 15,24 we investigated the secondary expansion capacity upon allogeneic restimulation in the absence of AKT-inhibition. Notably, all AKT-inhibited T cells expanded 2 to 10-fold better as compared to control T cells (Figure 2D, p  < 0.05).…”

“…Proliferated cells were isolated at day 7 of allo-MLR, and total RNA was isolated with the RNeasy Plus Mini Kit (cat#74134, Qiagen). Microarray analysis of control and AKT-inhibited CD8 + T cells was performed as previously described, 24 using the Whole Transcript Human Gene 1.0 ST arrays (cat#901085, Affymetrix). The raw data were imported into the Partek Genomincs Suite, normalized using the Robust Multi-array Average (RMA) method and log2 transformed.…”

“…Principal component analysis (PCA) and hierarchical clustering are presented based on Partek visualization program, using a 900 gene list from Gattinoni et al . 24 Enrichment of up- or down-regulated genes was examined with the parametric gene set enrichment analysis (GSEA). 49 Enriched gene sets were identified using 1000 permutations of the phenotype labels.…”