@article{310da8a2dd37400a80f242da4287d91d,
title = "Aging-associated HELIOS deficiency in naive CD4+ T cells alters chromatin remodeling and promotes effector cell responses",
abstract = "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.",
author = "Huimin Zhang and Jadhav, {Rohit R.} and Wenqiang Cao and Goronzy, {Isabel N.} and Zhao, {Tuantuan V.} and Jun Jin and Shozo Ohtsuki and Zhaolan Hu and Jose Morales and Greenleaf, {William J.} and Weyand, {Cornelia M.} and Goronzy, {J{\"o}rg J.}",
note = "Funding Information: This work was financially supported by the Brain Research Center, National Yang Ming Chiao Tung University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE), the Ministry of Science and Technology, Taiwan [MOST 106–2320-B-010-011-MY3, MOST 106–2923-B-010-001-MY3, MOST 108–2923-B-010-001-MY2, 108–2911-I-010-504, 108–2321-B-010-009-MY2,108–2320-B-010-026-MY3, and 108–2638-B-010-002-MY2 (to CCL); MOST-107-2314-B-010-021, 108–2314-B-010 -022 -MY3 & 110–2326-B-A49A-501 -MY3 (to SPC); MOST 108–2321-B-010-014-MY2, 108–2321-B-010-001-, 108–2314-B-010-023-MY3, 110–2321-B-010-005- & 111–2321-B-A49–004 - (to SJW)], Ministry of Health and Welfare, Taiwan [MOHW107-TDU-B-211-123001 and MOHW 108-TDU-B-211-133001] (to SJW), and Taipei Veterans General Hospital, Taiwan [VGH-106-D9–001-MY2–2 (to SJW) & V110C-102, V111C-158, V109D52–001-MY3–2, VGHUST110-G1–3-1 (to SPC)]. Funding Information: This work was supported by the National Institutes of Health (R01 AR042527, R01 HL117913, R01 AI108906, R01 HL142068 and P01 HL129941 to C.M.W. and R01 AI108891, R01 AG045779, U19 AI057266 and R01 AI129191 to J.J.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank E. Fischer from Harvard Medical School for providing the ALV2 compound, P. Li from the National Institutes of Health for providing processed ChIP-seq data files of human CD4+T cells, C. Gustafson and F. M{\"u}ller for suggestions on single-cell data analysis, X. Wang and F. Cao for suggestions on ATAC-seq time course analysis and the Stanford Genome Sequencing Service Center and Novogen for providing sequencing services. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2023",
month = jan,
doi = "10.1038/s41590-022-01369-x",
language = "English (US)",
volume = "24",
pages = "96--109",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "1",
}