Dataset Information

CD4+ virtual memory: Antigen-inexperienced T cells reside in the naive, regulatory, and memory T cell compartments at similar frequencies, implications for autoimmunity.

ABSTRACT: It is widely accepted that central and effector memory CD4+ T cells originate from naïve T cells after they have encountered their cognate antigen in the setting of appropriate co-stimulation. However, if this were true the diversity of T cell receptor (TCR) sequences within the naïve T cell compartment should be far greater than that of the memory T cell compartment, which is not supported by TCR sequencing data. Here we demonstrate that aged mice with far fewer naïve T cells, respond to the model antigen, hen eggwhite lysozyme (HEL), by utilizing the same TCR sequence as their younger counterparts. CD4+ T cell repertoire analysis of highly purified T cell populations from naive animals revealed that the HEL-specific clones displayed effector and central "memory" cell surface phenotypes even prior to having encountered their cognate antigen. Furthermore, HEL-inexperienced CD4+ T cells were found to reside within the naïve, regulatory, central memory, and effector memory T cell populations at similar frequencies and the majority of the CD4+ T cells within the regulatory and memory populations were unexpanded. These findings support a new paradigm for CD4+ T cell maturation in which a specific clone can undergo a differentiation process to exhibit a "memory" or regulatory phenotype without having undergone a clonal expansion event. It also demonstrates that a foreign-specific T cell is just as likely to reside within the regulatory T cell compartment as it would the naïve compartment, arguing against the specificity of the regulatory T cell compartment being skewed towards self-reactive T cell clones. Finally, we demonstrate that the same set of foreign and autoreactive CD4+ T cell clones are repetitively generated throughout adulthood. The latter observation argues against T cell-depleting strategies or autologous stem cell transplantation as therapies for autoimmunity-as the immune system has the ability to regenerate pathogenic clones.

SUBMITTER: Marusina AI

PROVIDER: S-EPMC6066671 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Publications

CD4<sup>+</sup> virtual memory: Antigen-inexperienced T cells reside in the naïve, regulatory, and memory T cell compartments at similar frequencies, implications for autoimmunity.

Marusina Alina I AI Ono Yoko Y Merleev Alexander A AA Shimoda Michiko M Ogawa Hiromi H Wang Elizabeth A EA Kondo Kayo K Olney Laura L Luxardi Guillaume G Miyamura Yoshinori Y Yilma Tilahun D TD Villalobos Itzel Bustos IB Bergstrom Jennifer W JW Kronenberg Daniel G DG Soulika Athena M AM Adamopoulos Iannis E IE Maverakis Emanual E

Journal of autoimmunity 20161125

It is widely accepted that central and effector memory CD4<sup>+</sup> T cells originate from naïve T cells after they have encountered their cognate antigen in the setting of appropriate co-stimulation. However, if this were true the diversity of T cell receptor (TCR) sequences within the naïve T cell compartment should be far greater than that of the memory T cell compartment, which is not supported by TCR sequencing data. Here we demonstrate that aged mice with far fewer naïve T cells, respon ...[more]

PMID: 27894837

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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

CD4+ virtual memory: Antigen-inexperienced T cells reside in the naive, regulatory, and memory T cell compartments at similar frequencies, implications for autoimmunity.

Publications

CD4<sup>+</sup> virtual memory: Antigen-inexperienced T cells reside in the naïve, regulatory, and memory T cell compartments at similar frequencies, implications for autoimmunity.

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