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The STAT5-IRF4-BATF pathway drives heightened epigenetic remodeling in naïve CD4⁺ T cell responses of older adults

Zhang, Huimin and Jadhav, Rohit R. and Cao, Wenqiang and Goronzy, Isabel N. and Jin, Jun and Greenleaf, William J. and Weyand, Cornelia M. and Goronzy, Jörg J. (2021) The STAT5-IRF4-BATF pathway drives heightened epigenetic remodeling in naïve CD4⁺ T cell responses of older adults. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20210831-171956165

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Abstract

T cell aging is a complex process combining the emergence of cellular defects with activation of adaptive mechanisms. Generation of T cell memory is impaired, while a low-inflammatory state is induced, in part due to effector T cells. To determine whether age-associated changes in T cell fate decisions occur early after T cell activation, we profiled the longitudinal transcriptional and epigenetic landscape induced by TCR stimulation comparing naïve CD4⁺ T cells from young and older adults. In spite of attenuated TCR signaling, activation-induced remodeling of the epigenome increased with age, culminating in heightened BATF and BLIMP1 activity. Single cell studies, integrating ATAC-seq and RNA-seq data, identified increases in dysfunctional and in effector T cells and a decrease in BACH2-expressing memory cell precursors. STAT5 activation, in part due to a decline in HELIOS and aberrant IL-2 receptor expression, accounted for the induction of transcription factor networks favoring effector cell differentiation.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2021.08.27.457205DOIDiscussion Paper
ORCID:
AuthorORCID
Zhang, Huimin0000-0003-1143-9388
Jadhav, Rohit R.0000-0002-2999-6329
Cao, Wenqiang0000-0002-5024-0817
Jin, Jun0000-0002-5018-144X
Greenleaf, William J.0000-0003-1409-3095
Weyand, Cornelia M.0000-0003-2230-9802
Goronzy, Jörg J.0000-0001-7670-1856
Alternate Title:The STAT5-IRF4-BATF pathway drives heightened epigenetic remodeling in naïve CD4+ T cell responses of older adults
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This version posted August 28, 2021. 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 Dr. Peng Li from the National Institutes of Health for providing the processed ChIP-seq data file of human CD4+ T cells. We thank Dr. Fabian Müller for suggestions on single cell data analysis. We thank the Stanford Genome Sequencing Service Center and Novogen for providing sequencing services. Author Contributions: H.Z., R.R.J., W.J.G., C.M.W. and J.J.G. designed research and interpreted data. H.Z., W.C. and J.J. 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. The authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest. Data Availability Statement Raw sequencing data have been deposited in SRA with the BioProject accession # PRJNA757466.
Funders:
Funding AgencyGrant Number
NIHR01 AR042527
NIHR01 HL117913
NIHR01 AI108906
NIHR01 HL142068
NIHP01 HL129941
NIHR01 AI108891
NIHR01 AG045779
NIHU19 AI057266
NIHR01 AI129191
Subject Keywords:Naïve T cells, aging, immune memory, T cell activation, single cell multiomics, epigenomics, inflammaging
DOI:10.1101/2021.08.27.457205
Record Number:CaltechAUTHORS:20210831-171956165
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210831-171956165
Official Citation:The STAT5-IRF4-BATF pathway drives heightened epigenetic remodeling in naïve CD4+ T cell responses of older adults. Huimin Zhang, Rohit R. Jadhav, Wenqiang Cao, Isabel N. Goronzy, Jun Jin, William J. Greenleaf, Cornelia M. Weyand, Jörg J. Goronzy. bioRxiv 2021.08.27.457205; doi: https://doi.org/10.1101/2021.08.27.457205
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110635
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:31 Aug 2021 18:10
Last Modified:16 Nov 2021 19:41

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