Aging-associated HELIOS deficiency in naive CD4 + T cells alters chromatin remodeling and promotes effector cell responses.
Huimin ZhangRohit R JadhavWenqiang CaoIsabel N GoronzyTuantuan V ZhaoJun JinShozo OhtsukiZhao-Lan HuJose MoralesWilliam J GreenleafCornelia M WeyandJorg J GoronzyPublished in: Nature immunology (2022)
Immune aging combines cellular defects in adaptive immunity with the activation of pathways causing a low-inflammatory state. Here we examined the influence of age on the kinetic changes in the epigenomic and transcriptional landscape induced by T cell receptor (TCR) stimulation in naive CD4 + T cells. Despite attenuated TCR signaling in older adults, TCR activation accelerated remodeling of the epigenome and induced transcription factor networks favoring effector cell differentiation. We identified increased phosphorylation of STAT5, at least in part due to aberrant IL-2 receptor and lower HELIOS expression, as upstream regulators. Human HELIOS-deficient, naive CD4 + T cells, when transferred into human-synovium-mouse chimeras, infiltrated tissues more efficiently. Inhibition of IL-2 or STAT5 activity in T cell responses of older adults restored the epigenetic response pattern to the one seen in young adults. In summary, reduced HELIOS expression in non-regulatory naive CD4 + T cells in older adults directs T cell fate decisions toward inflammatory effector cells that infiltrate tissue.
Keyphrases
- regulatory t cells
- transcription factor
- hiv infected
- endothelial cells
- gene expression
- poor prognosis
- physical activity
- young adults
- dendritic cells
- dna methylation
- cell fate
- high glucose
- single cell
- induced apoptosis
- binding protein
- oxidative stress
- cell proliferation
- induced pluripotent stem cells
- type iii
- pluripotent stem cells
- dna damage
- antiretroviral therapy
- drug induced
- long non coding rna
- bone marrow
- genome wide identification
- signaling pathway
- protein kinase
- heat shock protein