The STAT5-IRF4-BATF pathway drives heightened epigenetic remodeling in naïve CD4⁺ T cell responses of older adults
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.
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.Attached Files
Submitted - 2021.08.27.457205v1.full.pdf
Supplemental Material - media-1.pdf
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Additional details
- Alternative title
- The STAT5-IRF4-BATF pathway drives heightened epigenetic remodeling in naïve CD4+ T cell responses of older adults
- Eprint ID
- 110635
- Resolver ID
- CaltechAUTHORS:20210831-171956165
- R01 AR042527
- NIH
- R01 HL117913
- NIH
- R01 AI108906
- NIH
- R01 HL142068
- NIH
- P01 HL129941
- NIH
- R01 AI108891
- NIH
- R01 AG045779
- NIH
- U19 AI057266
- NIH
- R01 AI129191
- NIH
- Created
-
2021-08-31Created from EPrint's datestamp field
- Updated
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2021-11-16Created from EPrint's last_modified field