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Virtual memory CD8 T cells display unique functional properties.

ABSTRACT: Previous studies revealed the existence of foreign antigen-specific memory phenotype CD8 T cells in unimmunized mice. Considerable evidence suggests this population, termed "virtual memory" (VM) CD8 T cells, arise via physiological homeostatic mechanisms. However, the antigen-specific function of VM cells is poorly characterized, and hence their potential contribution to immune responses against pathogens is unclear. Here we show that naturally occurring, polyclonal VM cells have unique functional properties, distinct from either naïve or antigen-primed memory CD8 T cells. In striking contrast to conventional memory cells, VM cells showed poor T cell receptor-induced IFN-γ synthesis and preferentially differentiated into central memory phenotype cells after priming. Importantly, VM cells showed efficient control of Listeria monocytogenes infection, indicating memory-like capacity to eliminate certain pathogens. These data suggest naturally arising VM cells display unique functional traits, allowing them to form a bridge between the innate and adaptive phase of a response to pathogens.

SUBMITTER: Lee JY

PROVIDER: S-EPMC3746847 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Virtual memory CD8 T cells display unique functional properties.

Lee June-Yong JY Hamilton Sara E SE Akue Adovi D AD Hogquist Kristin A KA Jameson Stephen C SC

Proceedings of the National Academy of Sciences of the United States of America 20130729 33

Previous studies revealed the existence of foreign antigen-specific memory phenotype CD8 T cells in unimmunized mice. Considerable evidence suggests this population, termed "virtual memory" (VM) CD8 T cells, arise via physiological homeostatic mechanisms. However, the antigen-specific function of VM cells is poorly characterized, and hence their potential contribution to immune responses against pathogens is unclear. Here we show that naturally occurring, polyclonal VM cells have unique function ...[more]

PMID: 23898211

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Project description:BackgroundPrevious research in FMS-like tyrosine kinase 3 ligands (FLT3L) has primarily focused on their potential to generate dendritic cells (DCs) from bone marrow progenitors, with a limited understanding of how these cells affect CD8 T cell function. In this study, we further investigated the in vivo role of FLT3L for the immunomodulatory capabilities of CD8 T cells.MethodsAlbumin-conjugated FLT3L (Alb-FLT3L) was generated and applied for translational medicine purposes; here it was used to treat naïve C57BL/6 and OT1 mice for CD8 T cell response analysis. Syngeneic B16ova and E.G7ova mouse models were employed for adoptive cell transfer to evaluate the effects of Alb-FLT3L preconditioning of CD8 T cells on tumor progression. To uncover the underlying mechanisms of Alb-FLT3L modulation, we conducted bulk RNA-seq analysis of the CD44high CD8 T cells. STAT1-deficient mice were used to elucidate the functional roles of Alb-FLT3L in the modulation of T cells. Finally, antibody blockade of type one interferon signaling and in vitro coculture of plasmacytoid DCs (pDCs) with naive CD8 T cells was performed to determine the role of pDCs in mediating regulation of CD44high CD8 T cells.ResultsCD44high CD8 T cells were enhanced in C57BL/6 mice administrated with Alb-FLT3L. These CD8 T cells exhibited virtual memory features and had greater proliferative and effective functions. Notably, the adoptive transfer of CD44high naïve CD8 T cells into C57BL/6 mice with B16ova tumors led to significant tumor regression. RNA-seq analysis of the CD44high naïve CD8 T cells revealed FLT3L to induce CD44high CD8 T cells in a JAK-STAT1 signaling pathway-dependent manner, as supported by results indicating a decreased ability of FLT3L to enhance CD8 T cell proliferation in STAT1-deficient mice as compared to wild-type control mice. Moreover, antibody blockade of type one interferon signaling restricted the generation of FLT3L-induced CD44high CD8 T cells, while CD44 expression was able to be induced in naïve CD8 T cells cocultured with pDCs derived from FLT3L-treated mice. This suggests the crucial role of pDCs in mediating FLT3L regulation of CD44high CD8 T cells.ConclusionsThese findings provide critical insight and support the therapeutic potential of Alb-FLT3L as an immune modulator in preconditioning of naïve CD8 T cells for cancer immunotherapy.

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Virtual memory CD8 T cells display unique functional properties.

Publications

Virtual memory CD8 T cells display unique functional properties.

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