title: Phenotypic characteristics of aged CD4+CD28nullT lymphocytes are determined by changes in the whole-genome DNA methylation pattern.
abstract: Aging is associated with a progressive loss of the CD28 costimulatory molecule in CD4+lymphocytes (CD28nullT cells), which is accompanied by the acquisition of new biological and functional properties that give rise to an impaired immune response. The regulatory mechanisms that govern the appearance and function of this cell subset during aging and in several associated inflammatory disorders remain controversial. Here, we present the whole-genome DNA methylation and gene expression profiles of CD28nullT cells and its CD28+counterpart. A comparative analysis revealed that 296 genes are differentially methylated between the two cell subsets. A total of 160 genes associated with cytotoxicity (e.g. GRZB, TYROBP, and RUNX3) and cytokine/chemokine signaling (e.g. CX3CR1, CD27, and IL-1R) are demethylated in CD28nullT cells, while 136 de novo-methylated genes matched defects in the TCR signaling pathway (e.g. ITK, TXK, CD3G, and LCK). TCR-landscape analysis confirmed that CD28nullT cells have an oligo/monoclonal expansion over the polyclonal background of CD28+T cells, but feature a Vβ family repertoire specific to each individual. We reported that CD28nullT cells show a preactivation state characterized by a higher level of expression of inflammasome-related genes that leads to the release of IL-1β when activated. Overall, our results demonstrate that CD28nullT cells have a unique DNA methylation landscape, which is associated with differences in gene expression, contributing to the functionality of these cells. Understanding these epigenetic regulatory mechanisms could suggest novel therapeutic strategies to prevent the accumulation and activation of these cells during aging.
authors.affiliation: Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Suarez-Álvarez
authors.affiliation: Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Ramón M
authors.initials: RM
authors.lastname: Rodríguez
authors.affiliation: Genome Analysis Platform, CIC bioGUNE, Bizkaia Technological Technology Park, Derio, Spain.
authors.forename: Karin
authors.initials: K
authors.lastname: Schlangen
authors.affiliation: Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Aroa Baragaño
authors.initials: AB
authors.lastname: Raneros
authors.affiliation: Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Márquez-Kisinousky
authors.affiliation: Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Agustín F
authors.initials: AF
authors.lastname: Fernández
authors.affiliation: Department of Nephrology, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Díaz-Corte
authors.affiliation: Genome Analysis Platform, CIC bioGUNE, Bizkaia Technological Technology Park, Derio, Spain.|CIBERhed.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Aransay
authors.affiliation: Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Larrea
mesh_terms: D017209:Apoptosis / Q000235:genetics; D018106:CD28 Antigens / Q000378:metabolism*; D015704:CD4 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D016922:Cellular Senescence / Q000235:genetics* / Q000276:immunology*; D018899:CpG Islands / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D019175:DNA Methylation / Q000235:genetics*; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D007109:Immunity; D058847:Inflammasomes / Q000378:metabolism; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction
chemical_list: D018106:CD28 Antigens; D015704:CD4 Antigens; D058847:Inflammasomes; D011948:Receptors, Antigen, T-Cell
keywords: CD4+ CD28null T cells; DNA methylation; TCR signaling; aging; gene expression; inflammation