ABSTRACT
Respiratory viruses such as influenza are encountered multiple times through infection and/or vaccination and thus have the potential to shape immune cell phenotypes over time. In particular, memory T cell compartments may be affected, as both CD4+ and CD8+ T cell responses likely contribute to viral control. In this study, we assessed immune phenotypes using cytometry by time of flight in the peripheral blood of 22 humans with acute respiratory illness and 22 age-matched noninfected controls. In younger infected individuals (1-19 y of age), we found decreased B and NK cell frequencies and a shift toward more effector-like CD4+ and CD8+ T cell phenotypes, compared with young healthy controls. Significant differences between noninfected and infected older individuals (30-74 y of age) were not seen. We also observed a decrease in naive CD4+ T cells and CD27+CD8+ T cells as well as an increase in effector memory CD8+ T cells and NKT cells in noninfected individuals with age. When cell frequencies were regressed against age for infected versus noninfected subjects, significant differences in trends with age were observed for multiple cell types. These included B cells and various subsets of CD4+ and CD8+ T cells. We conclude that acute respiratory illness drives T cell differentiation and decreases circulating B cell frequencies preferentially in young compared with older individuals.
Subject(s)
CD8-Positive T-Lymphocytes , Influenza, Human , Humans , Cell Differentiation , Lymphocyte Activation , B-LymphocytesABSTRACT
Premature unblinding of individual participants is rarely reported in publications, but such unblinding can disrupt vaccine trials by causing worry and drop-out of other participants or "pseudo unblinding," in which participants or investigators over-interpret certain symptoms as being related to receiving an investigational product. This review summarizes appropriate reasons for unblinding in vaccine trials. Regulatory guidance could be improved by distinguishing guidance for vaccine trials from drug trials, with the recognition that unblinding individual participants in vaccine studies is rarely needed for management of adverse events following immunization.
Subject(s)
Vaccination , Vaccines , Humans , Vaccination/adverse effects , Vaccines/adverse effectsABSTRACT
In this work, we find that CD8+ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49+CD8+ regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8+ T cells efficiently eliminated pathogenic gliadin-specific CD4+ T cells from the leukocytes of celiac disease patients in vitro. We also find elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 patients, correlating with disease severity and vasculitis. Selective ablation of Ly49+CD8+ T cells in virus-infected mice led to autoimmunity after infection. Our results indicate that in both species, these regulatory CD8+ T cells act specifically to suppress pathogenic T cells in autoimmune and infectious diseases.
Subject(s)
Autoimmune Diseases , COVID-19 , Animals , CD8-Positive T-Lymphocytes , Humans , Mice , Receptors, KIR , T-Lymphocytes, RegulatoryABSTRACT
While many diseases of aging have been linked to the immunological system, immune metrics capable of identifying the most at-risk individuals are lacking. From the blood immunome of 1,001 individuals aged 8-96 years, we developed a deep-learning method based on patterns of systemic age-related inflammation. The resulting inflammatory clock of aging (iAge) tracked with multimorbidity, immunosenescence, frailty and cardiovascular aging, and is also associated with exceptional longevity in centenarians. The strongest contributor to iAge was the chemokine CXCL9, which was involved in cardiac aging, adverse cardiac remodeling and poor vascular function. Furthermore, aging endothelial cells in human and mice show loss of function, cellular senescence and hallmark phenotypes of arterial stiffness, all of which are reversed by silencing CXCL9. In conclusion, we identify a key role of CXCL9 in age-related chronic inflammation and derive a metric for multimorbidity that can be utilized for the early detection of age-related clinical phenotypes.
Subject(s)
Deep Learning , Frailty , Immunosenescence , Aged, 80 and over , Humans , Animals , Mice , Multimorbidity , Endothelial Cells , Aging , Inflammation/epidemiologyABSTRACT
Beginning in December of 2019, a novel coronavirus, SARS-CoV-2, emerged in China and is now a global pandemic with extensive morbidity and mortality. With the emergence of this threat, an unprecedented effort to develop vaccines against this virus began. As vaccines are now being introduced globally, we face the prospect of millions of people being vaccinated with multiple types of vaccines many of which use new vaccine platforms. Since medical events happen without vaccines, it will be important to know at what rate events occur in the background so that when adverse events are identified one has a frame of reference with which to compare the rates of these events so as to make an initial assessment as to whether there is a potential safety concern or not. Background rates vary over time, by geography, by sex, socioeconomic status and by age group. Here we describe two key steps for post-introduction safety evaluation of COVID-19 vaccines: Defining a dynamic list of Adverse Events of Special Interest (AESI) and establishing background rates for these AESI. We use multiple examples to illustrate use of rates and caveats for their use. In addition we discuss tools available from the Brighton Collaboration that facilitate case evaluation and understanding of AESI.
Subject(s)
COVID-19 , Vaccines , COVID-19 Vaccines , China/epidemiology , Humans , SARS-CoV-2 , Vaccines/adverse effectsABSTRACT
Chronic inflammation is thought to be a major cause of morbidity and mortality in aging, but whether similar mechanisms underlie dysfunction in infection-associated chronic inflammation is unclear. Here, we profiled the immune proteome, and cellular composition and signaling states in a cohort of aging individuals versus a set of HIV patients on long-term antiretroviral therapy therapy or hepatitis C virus (HCV) patients before and after sofosbuvir treatment. We found shared alterations in aging-associated and infection-associated chronic inflammation including T cell memory inflation, up-regulation of intracellular signaling pathways of inflammation, and diminished sensitivity to cytokines in lymphocytes and myeloid cells. In the HIV cohort, these dysregulations were evident despite viral suppression for over 10 y. Viral clearance in the HCV cohort partially restored cellular sensitivity to interferon-α, but many immune system alterations persisted for at least 1 y posttreatment. Our findings indicate that in the HIV and HCV cohorts, a broad remodeling and degradation of the immune system can persist for a year or more, even after the removal or drastic reduction of the pathogen load and that this shares some features of chronic inflammation in aging.
Subject(s)
Aging/immunology , HIV Infections/immunology , Hepatitis C/immunology , Viral Load , Adult , Aged , Aged, 80 and over , Antiretroviral Therapy, Highly Active , Antiviral Agents/therapeutic use , Cells, Cultured , Female , HIV Infections/drug therapy , HIV Infections/virology , Hepatitis C/drug therapy , Hepatitis C/virology , Humans , Interferon-alpha/metabolism , Lymphocytes/immunology , Male , Middle Aged , Myeloid Cells/immunology , Sofosbuvir/therapeutic useABSTRACT
This is a Brighton Collaboration Case Definition of the term "Vaccine Associated Enhanced Disease" to be utilized in the evaluation of adverse events following immunization. The Case Definition was developed by a group of experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of vaccines for SARS-CoV-2 vaccines and other emerging pathogens. The case definition format of the Brighton Collaboration was followed to develop a consensus definition and defined levels of certainty, after an exhaustive review of the literature and expert consultation. The document underwent peer review by the Brighton Collaboration Network and by selected Expert Reviewers prior to submission.
Subject(s)
COVID-19 , Vaccines , COVID-19 Vaccines , Data Collection , Humans , Immunization/adverse effects , SARS-CoV-2 , Vaccines/adverse effectsABSTRACT
A novel coronavirus (CoV), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 in Wuhan, China and has since spread as a global pandemic. Safe and effective vaccines are thus urgently needed to reduce the significant morbidity and mortality of Coronavirus Disease 2019 (COVID-19) disease and ease the major economic impact. There has been an unprecedented rapid response by vaccine developers with now over one hundred vaccine candidates in development and at least six having reached clinical trials. However, a major challenge during rapid development is to avoid safety issues both by thoughtful vaccine design and by thorough evaluation in a timely manner. A syndrome of "disease enhancement" has been reported in the past for a few viral vaccines where those immunized suffered increased severity or death when they later encountered the virus or were found to have an increased frequency of infection. Animal models allowed scientists to determine the underlying mechanism for the former in the case of Respiratory syncytial virus (RSV) vaccine and have been utilized to design and screen new RSV vaccine candidates. Because some Middle East respiratory syndrome (MERS) and SARS-CoV-1 vaccines have shown evidence of disease enhancement in some animal models, this is a particular concern for SARS-CoV-2 vaccines. To address this challenge, the Coalition for Epidemic Preparedness Innovations (CEPI) and the Brighton Collaboration (BC) Safety Platform for Emergency vACcines (SPEAC) convened a scientific working meeting on March 12 and 13, 2020 of experts in the field of vaccine immunology and coronaviruses to consider what vaccine designs could reduce safety concerns and how animal models and immunological assessments in early clinical trials can help to assess the risk. This report summarizes the evidence presented and provides considerations for safety assessment of COVID-19 vaccine candidates in accelerated vaccine development.
Subject(s)
Antibodies, Viral/adverse effects , Antibodies, Viral/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , Viral Vaccines/adverse effects , Viral Vaccines/immunology , Animals , Betacoronavirus/pathogenicity , COVID-19 , COVID-19 Vaccines , Clinical Trials as Topic , Coronavirus Infections/prevention & control , Coronavirus Infections/virology , Disease Models, Animal , Humans , Pandemics , Pneumonia, Viral/virology , Risk Assessment , SARS-CoV-2 , Severe Acute Respiratory Syndrome/immunologyABSTRACT
Antibody memory protects humans from many diseases. Protective antibody memory responses require activation of transcriptional programs, cell proliferation, and production of antigen-specific antibodies, but how these aspects of the response are coordinated is poorly understood. We profile the molecular and cellular features of the antibody response to influenza vaccination by integrating single-cell transcriptomics, longitudinal antibody repertoire sequencing, and antibody binding measurements. Single-cell transcriptional profiling reveals a program of memory B cell activation characterized by CD11c and T-bet expression associated with clonal expansion and differentiation toward effector function. Vaccination elicits an antibody clone, which rapidly acquired broad high-affinity hemagglutinin binding during affinity maturation. Unexpectedly, many antibody clones elicited by vaccination do not bind vaccine, demonstrating non-specific activation of bystander antibodies by influenza vaccination. These results offer insight into how molecular recognition, transcriptional programs, and clonal proliferation are coordinated in the human B cell repertoire during memory recall.
Subject(s)
Antibodies, Viral/immunology , B-Lymphocytes/immunology , Bystander Effect/immunology , Immunologic Memory , Influenza, Human/immunology , Lymphocyte Activation/immunology , Single-Cell Analysis , Transcriptome/genetics , Adolescent , Clone Cells , Gene Expression Regulation , Humans , Immunologic Memory/genetics , Influenza Vaccines/immunology , Influenza, Human/blood , Phenotype , Population Dynamics , Transcription, Genetic , VaccinationABSTRACT
The T cell repertoire in each individual includes T cell receptors (TCRs) of enormous sequence diversity through the pairing of diverse TCR α- and ß-chains, each generated by somatic recombination of paralogous gene segments. Whether the TCR repertoire contributes to susceptibility to infectious or autoimmune diseases in concert with disease-associated major histocompatibility complex (MHC) polymorphisms is unknown. Due to a lack in high-throughput technologies to sequence TCR α-ß pairs, current studies on whether the TCR repertoire is shaped by host genetics have so far relied only on single-chain analysis. Using a high-throughput single T cell sequencing technology, we obtained the largest paired TCRαß dataset so far, comprising 965,523 clonotypes from 15 healthy individuals including 6 monozygotic twin pairs. Public TCR α- and, to a lesser extent, TCR ß-chain sequences were common in all individuals. In contrast, sharing of entirely identical TCRαß amino acid sequences was very infrequent in unrelated individuals, but highly increased in twins, in particular in CD4 memory T cells. Based on nucleotide sequence identity, a subset of these shared clonotypes appeared to be the progeny of T cells that had been generated during fetal development and had persisted for more than 50 y. Additional shared TCRαß in twins were encoded by different nucleotide sequences, implying that genetic determinants impose structural constraints on thymic selection that favor the selection of TCR α-ß pairs with entire sequence identities.
Subject(s)
Receptors, Antigen, T-Cell, alpha-beta/genetics , Twins, Monozygotic/genetics , Adult , Amino Acid Sequence/genetics , Base Sequence/genetics , CD4-Positive T-Lymphocytes/metabolism , Datasets as Topic , Female , HLA Antigens/genetics , HLA Antigens/metabolism , High-Throughput Nucleotide Sequencing , Histocompatibility Testing , Humans , Immunologic Memory , Male , Middle Aged , Models, Genetic , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Sequence Analysis, DNA , Single-Cell AnalysisABSTRACT
Pregnant women are particularly susceptible to complications of influenza A virus infection, which may result from pregnancy-induced changes in the function of immune cells, including natural killer (NK) cells. To better understand NK cell function during pregnancy, we assessed the ability of the two main subsets of NK cells, CD56dim, and CD56bright NK cells, to respond to influenza-virus infected cells and tumor cells. During pregnancy, CD56dim and CD56bright NK cells displayed enhanced functional responses to both infected and tumor cells, with increased expression of degranulation markers and elevated frequency of NK cells producing IFN-γ. To better understand the mechanisms driving this enhanced function, we profiled CD56dim and CD56bright NK cells from pregnant and non-pregnant women using mass cytometry. NK cells from pregnant women displayed significantly increased expression of several functional and activation markers such as CD38 on both subsets and NKp46 on CD56dim NK cells. NK cells also displayed diminished expression of the chemokine receptor CXCR3 during pregnancy. Overall, these data demonstrate that functional and phenotypic shifts occur in NK cells during pregnancy that can influence the magnitude of the immune response to both infections and tumors.
Subject(s)
Killer Cells, Natural/immunology , Pregnancy/immunology , Adult , Cells, Cultured , Cohort Studies , Female , Humans , Pregnancy Complications, Infectious/immunology , Pregnancy Complications, Neoplastic/immunologyABSTRACT
Machine learning has the potential to identify novel biological factors underlying successful antibody responses to influenza vaccines. The first attempts have revealed a high level of complexity in establishing influenza immunity, and many different cellular and molecular components are involved. Of note is that the previously identified correlates of protection fail to account for the majority of individual responses across different age groups and influenza seasons. Challenges remain from the small sample sizes in most studies and from often limited data sets, such as transcriptomic data. Here we report the creation of a unified database, FluPRINT, to enable large-scale studies exploring the cellular and molecular underpinnings of successful antibody responses to influenza vaccines. Over 3,000 parameters were considered, including serological responses to influenza strains, serum cytokines, cell phenotypes, and cytokine stimulations. FluPRINT, facilitates the application of machine learning algorithms for data mining. The data are publicly available and represent a resource to uncover new markers and mechanisms that are important for influenza vaccine immunogenicity.
Subject(s)
Immune System , Immunogenicity, Vaccine , Influenza Vaccines/immunology , Machine Learning , Adolescent , Adult , Aged , Aged, 80 and over , Antibody Formation , Child , Child, Preschool , Cytokines/blood , Female , Hemagglutination Inhibition Tests , Humans , Immunophenotyping , Infant , Male , Middle Aged , Young AdultABSTRACT
BACKGROUND: Seasonal influenza results in significant morbidity and mortality worldwide, but the currently licensed inactivated vaccines generally have low vaccine efficacies and could be improved. In this phase 1 clinical trial, we compared seasonal influenza vaccine regimens with different priming strategies, prime-boost intervals, and administration routes to determine the impact of these variables on the resulting antibody response. METHODS: Between August 17, 2012 and January 25, 2013, four sites enrolled healthy adults 18-70 years of age. Subjects were randomized to receive one of the following vaccination regimens: trivalent hemagglutinin (HA) DNA prime followed by trivalent inactivated influenza vaccine (IIV3) boost with a 3.5 month interval (DNA-IIV3), IIV3 prime followed by IIV3 boost with a 10 month interval (IIV3-IIV3), or concurrent DNA and IIV3 prime followed by IIV3 boost with a 10 month interval (DNA/IIV3-IIV3). Each regimen was additionally stratified by an IIV3 administration route of either intramuscular (IM) or intradermal (ID). DNA vaccines were administered by a needle-free jet injector (Biojector). Study objectives included evaluating the safety and tolerability of each regimen and measuring the antibody response by hemagglutination inhibition (HAI). RESULTS: Three hundred and sixteen subjects enrolled. Local reactogenicity was mild to moderate in severity, with higher frequencies recorded following DNA vaccine administered by Biojector compared to IIV3 by either route (p <0.02 for pain, swelling, and redness) and following IIV3 by ID route compared to IM route (p <0.001 for swelling and redness). Systemic reactogenicity was similar between regimens. Though no overall differences were observed between regimens, the highest titers post boost were observed in the DNA-IIV3 group by ID route and in the IIV3-IIV3 group by IM route. CONCLUSIONS: All vaccination regimens were found to be safe and tolerable. While there were no overall differences between regimens, the DNA-IIV3 group by ID route, and the IIV3-IIV3 group by IM route, showed higher responses compared to the other same-route regimens.
Subject(s)
Hemagglutinins/administration & dosage , Influenza Vaccines/administration & dosage , Influenza, Human/prevention & control , Vaccines, DNA/administration & dosage , Administration, Intranasal , Adult , Aged , Female , Healthy Volunteers , Hemagglutinins/adverse effects , Hemagglutinins/immunology , Humans , Immunization, Secondary , Influenza Vaccines/adverse effects , Influenza Vaccines/immunology , Injections, Intradermal , Male , Middle Aged , Vaccines, DNA/adverse effects , Vaccines, DNA/immunology , Vaccines, Inactivated/administration & dosage , Vaccines, Inactivated/adverse effects , Vaccines, Inactivated/immunology , Young AdultABSTRACT
Machine learning holds considerable promise for understanding complex biological processes such as vaccine responses. Capturing interindividual variability is essential to increase the statistical power necessary for building more accurate predictive models. However, available approaches have difficulty coping with incomplete datasets which is often the case when combining studies. Additionally, there are hundreds of algorithms available and no simple way to find the optimal one. In this study, we developed Sequential Iterative Modeling "OverNight" (SIMON), an automated machine learning system that compares results from 128 different algorithms and is particularly suitable for datasets containing many missing values. We applied SIMON to data from five clinical studies of seasonal influenza vaccination. The results reveal previously unrecognized CD4+ and CD8+ T cell subsets strongly associated with a robust Ab response to influenza Ags. These results demonstrate that SIMON can greatly speed up the choice of analysis modalities. Hence, it is a highly useful approach for data-driven hypothesis generation from disparate clinical datasets. Our strategy could be used to gain biological insight from ever-expanding heterogeneous datasets that are publicly available.
Subject(s)
Data Mining , Influenza Vaccines/immunology , Influenza, Human/immunology , Machine Learning , Adolescent , Adult , Algorithms , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Child , Datasets as Topic , Female , Humans , Influenza, Human/prevention & control , Influenza, Human/virology , Male , T-Lymphocyte Subsets/immunology , Vaccination , Young AdultABSTRACT
Immune responses generally decline with age. However, the dynamics of this process at the individual level have not been characterized, hindering quantification of an individual's immune age. Here, we use multiple 'omics' technologies to capture population- and individual-level changes in the human immune system of 135 healthy adult individuals of different ages sampled longitudinally over a nine-year period. We observed high inter-individual variability in the rates of change of cellular frequencies that was dictated by their baseline values, allowing identification of steady-state levels toward which a cell subset converged and the ordered convergence of multiple cell subsets toward an older adult homeostasis. These data form a high-dimensional trajectory of immune aging (IMM-AGE) that describes a person's immune status better than chronological age. We show that the IMM-AGE score predicted all-cause mortality beyond well-established risk factors in the Framingham Heart Study, establishing its potential use in clinics for identification of patients at risk.
Subject(s)
Cytokines/immunology , Healthy Volunteers , Immunosenescence/immunology , Lymphocytes/immunology , Mortality , Adult , Aged , Aged, 80 and over , Aging/immunology , Female , Humans , Individuality , Longitudinal Studies , Male , Middle Aged , Multivariate Analysis , Phenotype , Proportional Hazards Models , Young AdultABSTRACT
Combining HLA-DQ-gluten tetramers with mass cytometry and RNA sequencing analysis, we find that gluten-specific CD4+ T cells in the blood and intestines of patients with celiac disease display a surprisingly rare phenotype. Cells with this phenotype are also elevated in patients with systemic sclerosis and systemic lupus erythematosus, suggesting a way to characterize CD4+ T cells specific for disease-driving antigens in multiple autoimmune conditions.
Subject(s)
Autoimmune Diseases/immunology , CD4-Positive T-Lymphocytes/immunology , Celiac Disease/immunology , Celiac Disease/classification , Glutens/immunology , HLA-DQ Antigens/immunology , Humans , Immunophenotyping , Intestines/immunology , Lupus Erythematosus, Systemic/immunology , Scleroderma, Systemic/immunology , T-Lymphocyte Subsets/classification , T-Lymphocyte Subsets/immunologyABSTRACT
Antibodies are created and refined by somatic evolution in B cell populations, which endows the human immune system with the ability to recognize and eliminate diverse pathogens. However, the evolutionary processes that sculpt antibody repertoires remain poorly understood. Here, using an unbiased repertoire-scale approach, we show that the population genetic signatures of evolution are evident in human B cell lineages and reveal how antibodies evolve somatically. We measured the dynamics and genetic diversity of B cell responses in five adults longitudinally before and after influenza vaccination using high-throughput antibody repertoire sequencing. We identified vaccine-responsive B cell lineages that carry signatures of selective sweeps driven by positive selection, and discovered that they often display evidence for selective sweeps favoring multiple subclones. We also found persistent B cell lineages that exhibit stable population dynamics and carry signatures of neutral drift. By exploiting the relationship between B cell fitness and antibody binding affinity, we demonstrate the potential for using phylogenetic approaches to identify antibodies with high binding affinity. This quantitative characterization reveals that antibody repertoires are shaped by an unexpectedly broad spectrum of evolutionary processes and shows how signatures of evolutionary history can be harnessed for antibody discovery and engineering.
Subject(s)
Antibodies/genetics , Selection, Genetic/genetics , Adult , B-Lymphocytes/physiology , Cell Lineage/genetics , Evolution, Molecular , Genetic Variation/genetics , Genetics, Population/methods , Humans , Longitudinal Studies , Phylogeny , Vaccination/methodsABSTRACT
Annual vaccination with influenza vaccines is recommended for protection against influenza in the United States. Past clinical studies and meta-analysis, however, have reported conflicting results on the benefits of annual vaccination. B-cell responses elicited following repeat influenza vaccinations over multiple seasons have not been examined in detail. We analyzed the B-cell and antibody (Ab) responses in volunteers vaccinated yearly, from 2010 or 2011 through 2014, with seasonal trivalent inactivated influenza vaccines. Statistical analyses were designed to help correct for possible bias due to reduced sample size in the later years of the study. We show that, after the second annual vaccination, the frequency of vaccine-specific plasmablasts and the binding reactivity of plasmablast-derived polyclonal Abs are reduced and do not increase in subsequent years. Similar trends are observed with the serum hemagglutination inhibition Ab response after each annual vaccination, as well as the binding reactivity of plasmablast-derived polyclonal Abs to the hemagglutinin of influenza A virus vaccine components, even with changes in the seasonal vaccine components during the study. Our findings indicate a diminished B-cell response to annual vaccination with seasonal trivalent influenza vaccine. These results emphasize the need for developing improved strategies to enhance the immunogenicity and efficacy of annual influenza vaccination.
Subject(s)
B-Lymphocytes/immunology , Influenza Vaccines/immunology , Influenza, Human/immunology , Adolescent , Adult , Antibodies, Viral/blood , Antibody Formation , Female , Hemagglutination Inhibition Tests , Humans , Influenza A virus/immunology , Influenza, Human/prevention & control , Male , Vaccination , Vaccines, Inactivated/immunologyABSTRACT
Post-translational modifications of histone proteins and exchanges of histone variants of chromatin are central to the regulation of nearly all DNA-templated biological processes. However, the degree and variability of chromatin modifications in specific human immune cells remain largely unknown. Here, we employ a highly multiplexed mass cytometry analysis to profile the global levels of a broad array of chromatin modifications in primary human immune cells at the single-cell level. Our data reveal markedly different cell-type- and hematopoietic-lineage-specific chromatin modification patterns. Differential analysis between younger and older adults shows that aging is associated with increased heterogeneity between individuals and elevated cell-to-cell variability in chromatin modifications. Analysis of a twin cohort unveils heritability of chromatin modifications and demonstrates that aging-related chromatin alterations are predominantly driven by non-heritable influences. Together, we present a powerful platform for chromatin and immunology research. Our discoveries highlight the profound impacts of aging on chromatin modifications.