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Expression analysis of human naïve and memory CD8 T cells at resting stage and following short-term stimulation

ABSTRACT: Memory T cells (TM) play a prominent role in protection and auto-immunity due to their ability to mount a more effective response than naïve T cells (TN). However, the molecular mechanisms underlying enhanced functionality of TM are not well defined, particularly in human TM. We examined the global gene expression profiles of human CD8+ TN and TM before and after stimulation. There were 1,284, 1,373 and 1,629 differentially expressed genes between TN and TM at 0 hr, 4 hr and 24 hr after stimulation, respectively, with more genes expressed to higher levels in TM. Genes rapidly up-regulated in TN cells were largely involved in nitrogen, nucleoside and amino acid metabolisms. In contrast, those in CD8+ TM were significantly enriched for immune-response-associated processes, including cytokine production, lymphocyte activation and chemotaxis. Multiple cytokines were rapidly up-regulated in TM cells, including effector cytokines known to be produced by CD8+ T cells and important for their functions, as well as regulatory cytokines, both pro- and anti-inflammatory, that are not typically produced by CD8+ T cells. These results provide new insights into molecular mechanisms that contribute to the enhanced functionality of human CD8+ TM and their prominent role in protection and auto-immunity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE79828 | GEO | 2016/04/01

SECONDARY ACCESSION(S): PRJNA317139

REPOSITORIES: GEO

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Project description:Memory T cells (TM) play a prominent role in protective and auto-immunity because they mount a more effective response than naïve T cells (TN), by rapidly expressing a large number of immune response genes upon stimulation. Previous studies have shown a correlation between increased histone acetylation levels and rapid gene expression at specific loci in CD8+ TM. However, the underlying mechanisms of histone acetylation remodeling in TM and its role in regulating global gene expression are not well defined, particularly in human TM cells. In this study, we examined the global level of histone acetylation and the expression of histone acetyltransferases and deacetylases , and found no differences between human CD8+ TN and TM cells. Through Genomegenome-wide mapping of the histone acetyltransferase p300 in human CD8+ TN and TM cells, recruitment of p300 was found to be positively correlated with the expression of 213 genes in TM and 516 genes in TN cells at rest, and was positively correlated with the expression of 556 genes in TM and 330 genes in TN cells after 4 hrs’ stimulation. Importantly, genes which have positive correlations between expression levels and p300 occupancy in TM were significantly enriched in effector functions of CD8+ T cells, while those in TN cells were over-presented in nucleic acid processing and cell differentiations. At IFNG locus, specifically, the recruitment of p300 was significantly higher in CD8+ TM than TN and cells that were correlated with increased levels of histone acetylation at this locus, and robust IFN-g expression by CD8+ TM cells. Selective inhibition of p300 and deletion of p300 binding sites within the IFNG promoter resulted in decreased histone acetylation at this locus and the lower expression level of IFN-g in CD8+ TM cells. These results suggest that recruitment of the histone acetyltransferase p300 modifies histone acetylation and allows rapid expression of IFNG, and likely a large set of immune response genes, in human CD8+ TM, which in turn contribute to the enhanced functionality of human CD8+ TM cells.

Project description:Some unicellular organisms exhibit collective decision-making through intercellular communication once a quorum of members sense an environmental stress. Whether T cells at different states of differentiation may also synchronize their behavior on a population basis through direct interactions remains unclear. We report that memory CD8+ T cells (TMem) directly interact with naive T cells (TN) during priming, affecting the phenotypic, functional, transcriptional and metabolic differentiation of TN-derived progeny. This previously unrecognized, contact and concentration-dependent interaction between naive (TN) and memory CD8+ T cells (TMem) directly enhanced TN effector differentiation through non-apoptotic Fas signaling resulting in downstream Akt pathway activation. TN primed with TMem exhibited significantly impaired persistence and antitumor activity compared with TN primed alone. Disruption of FasL-Fas signaling in TN cells limited differentiation and enhanced anti-tumor immunity while provision of exogenous FasL in the absence of TMem impaired anti-tumor immunity by augmenting TN differentiation. These findings reveal that the full therapeutic potential of TN-derived cells for adoptive immunotherapy requires physical separation from TMem prior to priming or antagonism of Fas-signaling. FACS-sorted in vitro differentiated TMem samples were without stimulation (0 hours) (n=3), and FACS-sorted in vitro differentiated TMem samples were stimulated using CD3-specific and CD28-specific antibodies and IL-2 for 18 (n=3) and 96 (n=3) hours. FACS-sorted naive Pmel-1 CD8+ T cell samples were without stimulation (0 hours) (n=3), and FACS-sorted TN-derived Pmel-1 CD8+ T cell samples were stimulated using CD3-specific and CD28-specific antibodies and IL-2 for 18 (n=3) and 96 (n=3) hours. FACS-sorted TN-derived Pmel-1 CD8+ T cell samples were stimulated in the presence of TMem using CD3-specific and CD28-specific antibodies and IL-2 for 18 (n=3) and 96 (n=3) hours. FACS-sorted in vitro differentiated TMem samples were stimulated in the presence of TN using CD3-specific and CD28-specific antibodies and IL-2 for 18 (n=3) and 96 (n=3) hours. All samples were done in triplicate as biological repeats.

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Expression analysis of human naïve and memory CD8 T cells at resting stage and following short-term stimulation

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