Trimodal single-cell profiling reveals a novel pediatric CD8αα+ T cell subset and broad age-related molecular reprogramming across the T cell compartment
Zachary Thomson, Ziyuan He, Elliott Swanson, Katherine Henderson, Cole Phalen, Samir Rachid Zaim, Mark-Phillip Pebworth, Lauren Okada, Alexander T. Heubeck, Charles R. Roll, Veronica Hernandez, Morgan Weiss, Palak C. Genge, Julian Reading, Josephine R. Giles, Sasikanth Manne, Jeanette Dougherty, Cristina Jasen, Allison R. Greenplate, Lynne A. Becker, Lucas T. Graybuck, Suhas Vasaikar, Gregory L. Szeto, Adam K. Savage, Cate Speake, Jane H. Buckner, Xiaojun Li, Thomas F. Bumol, E. John Wherry, Troy R. Torgerson, Laura A. Vella, Sarah E. Henrickson, Peter J. Skene, Claire E. Gustafson
Abstract
Abstract Age-associated changes in the T cell compartment are well described. However, limitations of current single-modal or bimodal single-cell assays, including flow cytometry, RNA-seq (RNA sequencing) and CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing), have restricted our ability to deconvolve more complex cellular and molecular changes. Here, we profile >300,000 single T cells from healthy children (aged 11–13 years) and older adults (aged 55–65 years) by using the trimodal assay TEA-seq (single-cell analysis of mRNA transcripts, surface protein epitopes and chromatin accessibility), which revealed that molecular programming of T cell subsets shifts toward a more activated basal state with age. Naive CD4 + T cells, considered relatively resistant to aging, exhibited pronounced transcriptional and epigenetic reprogramming. Moreover, we discovered a novel CD8αα + T cell subset lost with age that is epigenetically poised for rapid effector responses and has distinct inhibitory, costimulatory and tissue-homing properties. Together, these data reveal new insights into age-associated changes in the T cell compartment that may contribute to differential immune responses.