Abstract
Memory CD8 T lymphocyte populations are remarkably heterogeneous and differ in their ability to protect the host. In order to identify the whole range of qualities uniquely associated with protective memory cells we compared the gene expression signatures of two qualities of memory CD8 T cells sharing the same antigenic-specificity: protective (Influenza-induced, Flu-TM) and non-protective (peptide-induced, TIM) spleen memory CD8 T cells. Although Flu-TM and TIM express classical phenotypic memory markers and are polyfunctional, only Flu-TM protects against a lethal viral challenge. Protective memory CD8 T cells express a unique set of genes involved in migration and survival that correlate with their unique capacity to rapidly migrate within the infected lung parenchyma in response to influenza infection. We also enlighten a new set of poised genes expressed by protective cells that is strongly enriched in cytokines and chemokines such as Ccl1, Ccl9 and Gm-csf. CCL1 and GM-CSF genes are also poised in human memory CD8 T cells. These immune signatures are also induced by two other pathogens (vaccinia virus and Listeria monocytogenes). The immune signatures associated with immune protection were identified on circulating cells, i.e. those that are easily accessible for immuno-monitoring and could help predict vaccines efficacy.
Highlights
Memory T cells that displayed multiple effector functions such as cytokines, chemokine secretion or cytolytic activity markers, was a better predictor of protection than the frequency of IFN-γ-producing T cells, a parameter frequently used to assess memory cells frequencies[11]
This represents a substantial number of transferred naive CD8 T cells, the initial frequency of naive TCR-transgenic CD8 T cells does not influence functional properties of memory T cells and their ability to protect from re-challenge[13,23]
Using transcriptome approaches applied to different qualities of CD8 T cells, we have identified unique gene expression signatures that are associated with the capacity of memory cells to protect against a lethal influenza infection
Summary
Memory T cells that displayed multiple effector functions such as cytokines, chemokine secretion or cytolytic activity markers, was a better predictor of protection than the frequency of IFN-γ-producing T cells, a parameter frequently used to assess memory cells frequencies[11]. Memory cells have been analysed in response to tumour[15], at different locations following pathogen infection[16,17] or after stimulation[18] None of these studies has addressed the gene expression signature uniquely associated with protection. Since high affinity TCRs have been associated with memory response efficiency, we generated memory cell types using naive CD8 T cells harbouring the same antigenic specificity, using F5 TCR transgenic cells that are specific for NP68, an influenza nucleoprotein epitope. This system avoids the selection of CD8 T cell clones with different affinities in the different experimental models. We have identified gene signatures that are uniquely associated with Flu-TM and which correlate with their capacity to migrate more rapidly to the infected parenchyma and contain cytokines and chemokines such as CCL1, CCL9 and GM-CSF
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