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Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses.

ABSTRACT: The number of naive T cells decreases and susceptibility to new microbial infections increases with age. Here we describe a previously unknown subset of phenotypically naive human CD8(+) T cells that rapidly secreted multiple cytokines in response to persistent viral antigens but differed transcriptionally from memory and effector T cells. The frequency of these CD8(+) T cells, called 'memory T cells with a naive phenotype' (TMNP cells), increased with age and after severe acute infection and inversely correlated with the residual capacity of the immune system to respond to new infections with age. CD8(+) TMNP cells represent a potential new target for the immunotherapy of persistent infections and should be accounted for and subtracted from the naive pool if truly naive T cells are needed to respond to antigens.

SUBMITTER: Pulko V

PROVIDER: S-EPMC4955715 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses.

Pulko Vesna V Davies John S JS Martinez Carmine C Lanteri Marion C MC Busch Michael P MP Diamond Michael S MS Knox Kenneth K Bush Erin C EC Sims Peter A PA Sinari Shripad S Billheimer Dean D Haddad Elias K EK Murray Kristy O KO Wertheimer Anne M AM Nikolich-Žugich Janko J

Nature immunology 20160606 8

The number of naive T cells decreases and susceptibility to new microbial infections increases with age. Here we describe a previously unknown subset of phenotypically naive human CD8(+) T cells that rapidly secreted multiple cytokines in response to persistent viral antigens but differed transcriptionally from memory and effector T cells. The frequency of these CD8(+) T cells, called 'memory T cells with a naive phenotype' (TMNP cells), increased with age and after severe acute infection and in ...[more]

PMID: 27270402

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Project description:BACKGROUND:CD4+ T cells can be broadly divided into naïve and memory subsets, each of which are differentially impaired by the aging process. It is unclear if and how these differences are reflected at the transcriptomic level. We performed microarray profiling on RNA derived from naïve (CD44low) and memory (CD44high) CD4+ T cells derived from young (2-3 month) and old (28 month) mice, in order to better understand the mechanisms of age-related functional alterations in both subsets. We also performed follow-up bioinformatic analyses in order to determine the functional consequences of gene expression changes in both of these subsets, and identify regulatory factors potentially responsible for these changes. RESULTS:We found 185 and 328 genes differentially expressed (FDR???0.05) in young vs. old naïve and memory cells, respectively, with 50 genes differentially expressed in both subsets. Functional annotation analyses highlighted an increase in genes involved in apoptosis specific to aged naïve cells. Both subsets shared age-related increases in inflammatory signaling genes, along with a decrease in oxidative phosphorylation genes. Cis-regulatory analyses revealed enrichment of multiple transcription factor binding sites near genes with age-associated expression, in particular NF-?B and several forkhead box transcription factors. Enhancer associated histone modifications were enriched near genes down-regulated in naïve cells. Comparison of our results with previous mouse and human datasets indicates few overlapping genes overall, but suggest consistent up-regulation of Casp1 and Il1r2, and down-regulation of Foxp1 in both mouse and human CD4+ T cells. CONCLUSIONS:The transcriptomes of naïve and memory CD4+ T cells are distinctly affected by the aging process. However, both subsets exhibit a common increase inflammatory genes and decrease in oxidative phosphorylation genes. NF-?B, forkhead box, and Myc transcription factors are implicated as upstream regulators of these gene expression changes in both subsets, with enhancer histone modifications potentially driving unique changes unique to naïve cells. Finally we conclude that there is little overlap in age-related gene expression changes between humans and mice; however, age-related alterations in a small subset of genes may be conserved.

Dataset Information

Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses.

Publications

Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses.

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