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SCIENCE IMMUNOLOGY | RESEARCH RESOURCE IMMUNOGENOMICS 2017 © The Authors, some rights reserved; exclusive licensee Epigenomics of human CD8 T cell differentiation American Association for the Advancement and aging of Science. David M. Moskowitz,1,2* David W. Zhang,1,3,4* Bin Hu,3,4 Sabine Le Saux,3,4 Rolando E. Yanes,3,4 Zhongde Ye,3,4 Jason D. Buenrostro,1,5 Cornelia M. Weyand,3,4 William J. Greenleaf,1†‡ Jörg J. Goronzy 3,4†‡ The efficacy of the adaptive immune response declines markedly with age, but the cell-intrinsic mechanisms driving immune aging in humans remain poorly understood. Immune aging is characterized by a loss of self-renewing naïve cells and the accumulation of differentiated but dysfunctional cells within the CD8 T cell compartment. Using the assay for transposase-accessible chromatin using sequencing, we inferred that the transcription factor binding activities cor- related with naïve and central and effector memory CD8 T cell states in young adults. Integrating our results with RNA sequencing, we identified transcription networks associated with CD8 T cell differentiation, with prominent roles impli- Downloaded from cated for BATF, ETS1, Eomes, and Sp1. Extending our analysis to aged humans, we found that the differences between the memory and naïve CD8 T cell subsets were largely preserved across age but that naïve and central memory cells from older individuals exhibited a shift toward more differentiated patterns of chromatin openness. In addition, aged naïve cells displayed a loss in chromatin accessibility at gene promoters, largely associated with a decrease in nuclear respiratory factor 1 (NRF1) binding. This shift was implicated in a marked drop-off in the ability of the aged naïve cells to transcribe respiratory chain genes, which may explain the reduced capacity of oxidative phosphorylation in older naïve cells. Our findings identify BATF- and NRF1-driven gene regulation as potential targets for delaying CD8 T cell http://immunology.sciencemag.org/ aging and restoring function. INTRODUCTION respond to antigenic stimulation (12). Limited genome-wide epigene- Aging is a ubiquitous biological process that drastically alters phys- tic studies have been performed on human CD8 T cell subsets; they iological function. Correspondingly, immune competency erodes have not comprehensively profiled chromatin accessibility in naïve, with age, leading to higher incidences of malignancies and increased EM, and CM compartments, nor have they examined the baseline morbidity and mortality from infections (1, 2). Much of this decline regulatory landscape for age-related dysfunction (13–15). has been attributed to a breakdown in T cell homeostasis, degrading Here, we report the genome-wide maps of chromatin accessibil- the competence of the central mediator of adaptive immunity (3, 4). ity in purified CD8 T cell subsets from age-segregated human donors. In the absence of thymic production, T cell renewal in humans is These data enabled us to define the changes across differentiation by entirely driven by the proliferation of peripheral naïve T cells (5). comparing naïve, EM, and CM cells and then to determine how those by guest on March 1, 2017 This homeostatic proliferation is similar across naïve CD4 and CD8 regulatory programs, as well as the subsets’ baseline chromatin land- T cells, independent of age (6), and maintains a diverse naïve T cell scapes, differ with age. Our results describe immune aging of CD8 repertoire in aged individuals (7). However, although the CD4 T cell naïve and CM T cells as a shift toward a more differentiated state, compartment is stable, age drastically affects the distribution of CD8 coupled with an erosion of chromatin accessibility at key promoters, subsets, causing a diminution of naïve and central memory (CM) in part mediated by a loss of nuclear respiratory factor 1 (NRF1) cells and an expansion of effector memory (EM) cells (8). In addi- binding. tion, naïve T cells develop functional defects with age that may relate to replicative stress induced by homeostatic turnover (9). Characterizing these cell-intrinsic drivers of T cell aging and their relationship to dif- RESULTS ferentiation is critical in identifying and combating immune aging. Genome-wide mapping of chromatin accessibility in CD8 Changes to the epigenetic landscape are hallmarks of both aging T cell subsets and differentiation and encompass chromatin remodeling, histone Using the assay for transposase-accessible chromatin using se- modifications, and DNA methylation (10, 11). Substantial revisions quencing (ATAC-seq) (16, 17), we generated genome-wide maps of to the epigenetic landscape are required for naïve T cells to lose their chromatin accessibility in three human CD8 T cell subsets, purified stem cell–like attributes and develop into memory cells that rapidly by sorting peripheral blood mononuclear cells (PBMCs): naïve (CD28hiCD45RAhiCD62Lhi), CM (CD45RAloCD62Lhi), and EM lo lo 1Department of Genetics, Stanford University School of Medicine, Stanford, CA (CD45RA CD62L ; Fig. 1A and fig. S1). The PBMCs were isolated 94305, USA. 2Biomedical Informatics Training Program, Stanford University School from 10 healthy individuals, comprising 5 donors under age 35 years of Medicine, Stanford, CA 94305, USA. 3Division of Immunology and Rheumatology, 4 (“young”; 2 males and 3 females) and 5 over age 60 years (“old”; 3 males Department of Medicine, Stanford University, Stanford, CA 94305, USA. Department lo hi of Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94306, USA. and 2 females). We excluded terminally differentiated CD28 CD45RA 5Program in Epithelial Biology and the Howard Hughes Medical Institute, Stanford effector T cells, which mostly contain oligoclonally expanded herpes University School of Medicine, Stanford, CA 94305, USA. virus–specific cells, to focus on age-related chromatin changes rather *These authors contributed equally to this work. than changes induced by chronic viral stimulation. To support the †Corresponding author. Email: [email protected] (J.J.G.); wjg@stanford. edu (W.J.G.) functional relevance of the chromatin openness patterns we identified, we ‡These authors contributed equally to this work. also performed RNA sequencing (RNA-seq) in each of the T cell subsets. Moskowitz et al., Sci. Immunol. 2, eaag0192 (2017) 17 February 2017 1 of 13 SCIENCE IMMUNOLOGY | RESEARCH RESOURCE A CD8 näive CD8 central memory CD8 effector memory CD45RA+/CD62L+/CD28+ CD45RA–/CD62L+ CD45RA–/CD62L– CD45RA CD62L chr2:87,040 kb 87,010 kb chr12:6,900 kb 6,930 kb chr12:68,554 kb 68,548 kb chr14:25,104 kb 25,098 kb B Downloaded from 45.9 45.9 17.9 17.9 CD8 näive 0 0 0 0 45.9 45.9 17.9 17.9 CD8 CM 0 0 0 0 45.9 45.9 17.9 17.9 http://immunology.sciencemag.org/ CD8 EM 0 0 0 0 RefSeq genes CD8A CD4 IFNG GZMB CD 100 150 Na Na Na Count 0 Na 0.5 0.9 Na Naïve Na Class Na 75 Na Repetitive Na Na Heterochromatin/ CM repressed CM by guest on March 1, 2017 CM Transcribed CM 50 CM CM Enhancer CM CM CM Poised CM EM Promoter CM 25 EM EM EM ChromHMM annotation (percentage) EM EM EM EM EM 0 EM Naive CD8 T cells, ATAC−seq EM genome-wide peaks Fig. 1. ATAC-seq open chromatin maps capture characteristic signatures that correlate with phenotypically defined CD8 T cell subsets. (A) T cells were sorted into naïve (CD28hiCD45RAhiCD62Lhi), CM (CD45RAloCD62Lhi), and EM (CD45RAloCD62Llo) CD8 T cell subsets, as shown in fig. S1. Contour plots show purity of sorted popula- tions. (B) ATAC-seq signal tracks in naïve, CM, and EM subsets at selected functionally relevant genes (CD8, CD4, IFNG, and GZMB). Small boxes in gene diagrams (bottom) represent exons. Each subset’s count is aggregated across the 10 constituent donors. The y axes are in units of reads per million reads in peaks. (C) Proportion of chroma- tin states in naïve CD8 T cells, genome-wide (left), and for ATAC-seq peaks (right). Chromatin states were called by the Roadmap Epigenomics Project using ChromHMM, and we aggregated the state calls over functionally related subclasses. Percentages are as fractions of base pairs. (D) Heat map of Spearman correlation coefficients of openness between naïve (Na), CM, and EM samples. Dendrograms indicate results from consensus clustering. Sequencing read density at phenotype-defining genes confirmed Across all three subsets, we identified a total of 64,089 distinct chro- successful transposition in each subset, with accessible chromatin at the matin accessibility peaks. Using predictions of chromatin states in CD8A locus and minimal accessibility at the CD4 locus (Fig. 1B). IFNG naïve CD8 T cells from the Roadmap Epigenomics Project (18), we ob - and GZMB, which are more rapidly inducible in memory T cells after served that the peaks were concentrated at promoters and enhancers, activation, were more open in CM and EM than naïve cells. and depleted at heterochromatic regions (Fig. 1C). Hierarchical clustering Moskowitz et al., Sci. Immunol. 2, eaag0192 (2017) 17 February 2017 2 of 13 SCIENCE IMMUNOLOGY | RESEARCH RESOURCE of the peaks segregated the three T cell subsets (Fig. 1D), with the two for several members of the bZIP, T-box, and RUNT TF families among memory populations clustering more closely with each other than the most significantly enriched (table S1). Our top hits encompassed with the naïve population. To mitigate the impact of donor heteroge- known regulators of T cell differentiation and development, such as neity, we excluded sex chromosomes, which have been shown to be a Eomes and TBX21 (T-bet) (P < 10−66) (24). The TF family with the major site of interindividual variation in chromatin accessibility (19). greatest representation was bZIP, which includes Jun-AP1 and BATF, To uncover the chromatin accessibility landscapes underlying both critical to T cell differentiation (25). These TFs were also more naïve and memory cell identity in the young, we identified loci of dif- expressed in EM than naïve.
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