BCL11B
B-cell lymphoma/leukemia 11B (BCL-11B) (B-cell CLL/lymphoma 11B) (COUP-TF-interacting protein 2) (Radiation-induced tumor suppressor gene 1 protein) (hRit1) [CTIP2] [RIT1]
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Several evidences indicate that aging negatively affects the effectiveness of influenza vaccination. Although it is well established that immunosenescence has an important role in vaccination response, the molecular pathways underlying this process are largely unknown. Given the importance of epigenetic remodeling in aging, here we analyzed the relationship between responsiveness to influenza vaccination and DNA methylation profiles in healthy subjects of different ages. Peripheral blood mononuclear cells were collected from 44 subjects (age range: 19-90 years old) immediately before influenza vaccination. Subjects were subsequently classified as responders or non-responders according to hemagglutination inhibition assay 4-6 weeks after the vaccination. Baseline whole genome DNA methylation in peripheral blood mononuclear cells was analyzed using the Illumina® Infinium 450 k microarray. Differential methylation analysis between the two groups (responders and non-responders) was performed through an analysis of variance, correcting for age, sex and batch. We identified 83 CpG sites having a nominal p-value <.001 and absolute difference in DNA methylation of at least 0.05 between the two groups. For some CpG sites, we observed age-dependent decrease or increase in methylation, which in some cases was specific for the responders and non-responders groups. Finally, we divided the cohort in two subgroups including younger (age < 50) and older (age ≥ 50) subjects and compared DNA methylation between responders and non-responders, correcting for sex and batch in each subgroup. We identified 142 differentially methylated CpG sites in the young subgroup and 305 in the old subgroup, suggesting a larger epigenetic remodeling at older ages. Interestingly, some of the differentially methylated probes mapped in genes involved in immunosenescence (CD40) and in innate immunity responses (CXCL16, ULK1, BCL11B, BTC). In conclusion, the analysis of epigenetic landscape can shed light on the biological basis of vaccine responsiveness during aging, possibly providing new appropriate biomarkers of this process.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- DNA Methylation
- Epigenesis, Genetic
- Female
- Genome-Wide Association Study
- Humans
- Immunity, Innate
- Immunogenicity, Vaccine
- Immunosenescence
- Influenza Vaccines
- Influenza, Human
- Leukocytes, Mononuclear
- Male
- Middle Aged
- Young Adult
Keywords
- Aging
- DNA methylation
- Immunosenescence
- Influenza vaccination
Human ageing affects the immune system resulting in an overall decline in immunocompetence. Although all immune cells are affected during aging, the functional capacity of T cells is most influenced and is linked to decreased responsiveness to infections and impaired differentiation. We studied age-related changes in DNA methylation and gene expression in CD4 and CD8 T cells from younger and older individuals. We observed marked difference between T cell subsets, with increased number of methylation changes and higher methylome variation in CD8 T cells with age. The majority of age-related hypermethylated sites were located at CpG islands of silent genes and enriched for repressive histone marks. Specifically, in CD8 T cell subset we identified strong inverse correlation between methylation and expression levels in genes associated with T cell mediated immune response (LGALS1, IFNG, CCL5, GZMH, CCR7, CD27 and CD248) and differentiation (SATB1, TCF7, BCL11B and RUNX3). Our results thus suggest the link between age-related epigenetic changes and impaired T cell function.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cell Differentiation
- Cell Lineage
- CpG Islands
- DNA Methylation
- Gene Expression Regulation
- Histone Code
- Humans
- Immunity
- Middle Aged
- Transcription, Genetic
- Young Adult