Aging-associated HELIOS deficiency in naive CD4⁺ T cells alters chromatin remodeling and promotes effector cell responses

Creators: Zhang, Huimin; Jadhav, Rohit R.; Cao, Wenqiang; Goronzy, Isabel N.; Zhao, Tuantuan V.; Jin, Jun; Ohtsuki, Shozo; Hu, Zhaolan; Morales, Jose; Greenleaf, William J.; Weyand, Cornelia M.; Goronzy, Jörg J.

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.

Additional 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. Müller 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. Contributions. H.Z., R.R.J., W.J.G., C.M.W. and J.J.G. designed the research and interpreted data. H.Z., W.C., T.Z., J.J., S.O., J.M. and Z.H. performed experimental work. R.R.J. and I.N.G. analyzed high-throughput data. H.Z., R.R.J. and J.J.G. wrote the manuscript. Data availability. Raw sequencing data have been deposited in SRA with the BioProject accession no. PRJNA757466. Raw experimental data will be provided by the corresponding author upon request. Source data are provided with this paper. Competing interests. W.J.G. has affiliations with 10x Genomics (consultant). The other authors declare no competing interests.

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