Nan-ping Weng

Nan-ping Weng
National Institute on Aging · Laboratory of Molecular Biology and Immunology (LMBI)

MD, PhD

About

156
Publications
13,692
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8,429
Citations
Citations since 2017
55 Research Items
2857 Citations
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20172018201920202021202220230100200300400500
20172018201920202021202220230100200300400500

Publications

Publications (156)
Preprint
Full-text available
Age-associated DNA methylation in blood cells convey information on health status. However, the mechanisms that drive these changes in circulating cells and their relationships to gene regulation are unknown. We identified age-associated DNA methylation sites in six purified blood borne immune cell types (naïve B, naïve CD4+ and CD8+ T cells, granu...
Article
Full-text available
Lysine specific methyltransferase 2D (Kmt2d) catalyzes the mono-methylation of histone 3 lysine 4 (H3K4me1) and plays a critical role in regulatory T cell generation via modulating Foxp3 gene expression. Here we report a role of Kmt2d in naïve CD8 ⁺ T cell generation and survival. In the absence of Kmt2d , the number of CD8 ⁺ T cells, particularly...
Article
Full-text available
Background Cytomegalovirus (CMV) infection leads to effector memory CD8⁺ T cell expansion and is associated with immune dysfunction in older adults. However, the molecular alterations of CMV-specific CD8⁺ T cells in CMV infected healthy young and middle-aged adults has not been fully characterized. Results We compared CD8⁺ T cells specific for a C...
Preprint
Intradermal delivery of self-replicating RNA (srRNA) is a promising vaccine platform. Considering that human skin temperature is around 33°C, lower than core body temperature of 37°C, we have developed an srRNA that functions optimally at skin temperature and is inactivated at or above 37°C as a safety switch. This temperature-controllable srRNA (c...
Article
Full-text available
The decline of CD8+ T cell functions contributes to deteriorating health with aging, but the mechanisms that underlie this phenomenon are not well understood. We use single-cell RNA sequencing with both cross-sectional and longitudinal samples to assess how human CD8+ T cell heterogeneity and transcriptomes change over nine decades of life. Eleven...
Article
Full-text available
A diverse T cell receptor (TCR) repertoire is essential for protection against a variety of pathogens, and TCR repertoire size is believed to decline with age. However, the precise size of human TCR repertoires, in both total and subsets of T cells, as well as their changes with age, are not fully characterized. We conducted a longitudinal analysis...
Article
Influenza A virus (IAV) is a major human pathogen that causes seasonal infections worldwide. IAV-specific CD8+ T-cell response provides an essential part of immune protection against IAV infections. In HLA-A2+ humans, the dominant epitope on IAV is matrix protein M1 residues 58–66 (GILGFVFTL, referred to as GIL). Here, we investigated the TCR reper...
Article
Long-term immunity against infections and effective response to vaccination are dependent on remarkable and unique feature of lymphocytes referred as “memory generation”. Despite having multiple mice studies focused on naïve to memory transition of lymphocytes our understanding of human naïve and memory properties is limited. In this study we explo...
Article
COVID-19, an infectious disease caused by SARS-CoV-2, has given rise to the current global pandemic. Despite the number of infections nearing 300 million people worldwide, CD8+ T cells against SARS-CoV-2 in COVID-19 convalescent, vaccinated, and healthy adults and their changes with age have not been fully characterized. Here, we report the frequen...
Article
Full-text available
The rapidity of SARS-CoV-2 vaccination around the world has substantially reduced the number of new cases of COVID-19 and their severity in highly vaccinated countries. The unanticipated efficacy of SARS-CoV-2 vaccines in older adults has been very encouraging but the longevity of vaccine immunity is currently unknown and protection against emergin...
Article
Epigenetic reprogramming underlies specification of immune cell lineages, but patterns that uniquely define immune cell types and the mechanisms by which they are established remain unclear. Here, we identified lineage-specific DNA methylation signatures of six immune cell types from human peripheral blood and determined their relationship to other...
Article
Full-text available
Abstract The emergence of SARS-CoV-2 and its inordinately rapid spread is posing severe challenges to the wellbeing of millions of people worldwide, health care systems and the global economy. While many younger people experience no or mild symptoms on infection, older adults are highly susceptible to life-threatening respiratory and systemic condi...
Article
Stimulation of human primary T cells with immobilized anti-CD3 and anti-CD28 Abs in vitro provide a system to study T cell activation and proliferation and an avenue for expanding T cells for immunotherapy. Magnetic beads conjugated with anti-CD3 and anti-CD28 Abs (Dynabeads Human T-Activator [D-TCA]) have been a golden standard for stimulating hum...
Article
Anti-CD3 and anti-CD28 antibodies are a method of choice for general and physiological activation of human primary T cells in vitro. Here we report a comparison of the growth, cell death, and cytokine production of anti-CD3 and anti-CD28 antibodies conjugated with lipid microbubbles (MB-TCA) and the standard Dynal beads (D-TCA). In 56-day cultures...
Article
Full-text available
The Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing (GESTALT) study is designed to understand the basis of immune dysfunction that accompanies human aging. Twelve immune cell subsets were purified from hundred healthy donors of age range 20 – 90 and used for transcriptomic, proteomic and epigenomic analyses. Additionally...
Article
Human aging is associated with low grade chronic inflammation termed, inflammaging, which is a significant risk factor for morbidity and mortality in elderly population. The innate immune system is implicated as master regulator of this process via expression of cytokines and other key mediators. We used ATAC-seq to identify chromatin signatures in...
Article
Full-text available
Antinuclear antibodies (ANA), a marker of self-reactivity to DNA and other nuclear antigens, are present in several autoimmune diseases and have been observed in healthy persons in the absence of autoimmune disease. ANA prevalence is higher in women and older adults, but the health implications of ANA in middle- to older-aged adults are unknown. Im...
Article
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Thymic regulatory T cells (tTreg) are critical in the maintenance of normal T cell immunity and tolerance. The role of TCR in tTreg selection remains incompletely understood. In this study, we assessed TCRα and TCRβ sequences of mouse tTreg and thymic conventional CD4+ T cells (Tconv) by high-throughput sequencing. We identified αβ TCR sequences th...
Article
Full-text available
Ageing has a profound detrimental impact on almost all living organisms. Immune systems play a particularly important role in protection against external challenges (pathogens) and internal insults (cancer) but their protective capacity commonly wanes with advancing age. With the rapid increase in the numbers of older people around the world, resea...
Article
Objective: The present study investigates whether associations between telomere length (TL) and cognitive performance across multiple domains are moderated by poverty status and race. Method: Participants were 325 African American and White urban-dwelling adults (M age = 47.9 years; 49.5% African American; 50.2% female; 48.9% living in poverty)...
Article
Telomeres are essential for chromosomal integrity. Telomere shortening during cell division restricts cellular proliferative capacity and leads to cellular senescence when critically shortened telomere lengths are reached. Similar to hematopoietic stem cells, T cells can upregulate telomerase activity to compensate for telomere loss incurred during...
Article
Full-text available
Maintenance of telomeres is essential for preserving T cell proliferative responses yet the precise role of telomerase in human T cell differentiation, function, and aging is not fully understood. Here we analyzed human telomerase reverse transcriptase (hTERT) expression and telomerase activity in six T cell subsets from 111 human adults and found...
Article
Age-associated increases in antinuclear antibodies (ANA) in the general population are commonly noted but the mechanisms underlying this observation are unclear. This study aims to evaluate whether shorter peripheral blood mononuclear cell (PBMC) telomere length, a marker of more advanced biological age, is associated with ANA positivity prevalence...
Article
Aging of immune system is characterized by progressive decline of physiological and cellular function of T cells, leading to a reduced immune function in the old. Recent studies of naïve T cells from young and old mice have identified age-related altered gene expressions, but the mechanisms underlying age associated changes of naïve T cells remain...
Article
Full-text available
The αβ T cell receptor (TCR) repertoire on mature T cells is selected in the thymus, but the basis for thymic selection of MHC-restricted TCRs from a randomly generated pre-selection repertoire is not known. Here we perform comparative repertoire sequence analyses of pre-selection and post-selection TCR from multiple MHC-sufficient and MHC-deficien...
Article
Objective: Studies have linked self-reported discrimination to telomere attrition, a biological marker of accelerated cellular aging. However, it is unknown whether intersections between social categories-race, socioeconomic status (SES), sex, and age-influence the association of varying forms of discrimination with telomere length. We examined th...
Article
To understand the role of telomerase in T cell differentiation and function, we analyzed human telomerase reverse transcriptase (hTERT) mRNA expression and telomerase activity in six T cell subsets from 85 healthy human donors (aged 17–82 years old). We found that levels of hTERT mRNA and telomerase activity were higher in CD4 T cell subsets as com...
Article
Aging of immune system is characterized by progressive decline of physiological and cellular function of T cells. Recent studies of naïve T cells from young and old mice have identified age-related altered gene expressions but the mechanisms underlying age associated changes of naïve T cells remain poorly understood. Here we compared the transcript...
Article
Lysine specific methyl-transferase 2D (Kmt2d) catalyzes the mono-methylation of histone 3 lysine 4 (H3K4me1) and play a critical role in enhancer-mediated gene expression regulation. However, its role in CD8 T cell development and differentiation has not been addressed. Here, we analyzed a T-cell specific KMT2D knockout mouse (KMT2Dfl/flCD4cre+) an...
Article
Full-text available
Transition from resting to cell cycle in response to antigenic stimulation is an essential step for naïve CD8+ T cells to differentiate to effector and memory cells. Leaving the resting state requires dramatic changes of chromatin status in the key cell cycle inhibitors but the details of these concerted events are not fully elucidated. Here, we sh...
Data
Gene expression profiles in Ezh2-deficient CD8+ T cells. Wild type or Ezh2-c-KO CD8+ naïve T cells were stimulated with anti-CD3 and anti-CD28 in vitro, and collected at different time points post-stimulation for qPCR analysis. The gene expression level was normalized to the level of Rpl32, and further normalized to the unstimulated wild type sampl...
Data
Validation of Ezh2 deletion in naïve CD8+ T cells from Ezh2-g-KO mice. (A,B) WT or Ezh2-g-KO CD8+ naïve T cells were isolated, labeled with CellTrace Violet and stimulated with anti-CD3 and anti-CD28 in vitro for 4 days. (A) YFP expression was detected in the divided Ezh2-g-KO CD8+ T cells. (B) The YFP+ divided cells in Ezh2-g-KO and YFP- divided c...
Data
Live Imaging of naïve CD8+ T cells of Ezh2-c-KO mice. Time lapse movie (2 fps) of overlaid DIC and Far Red (CellTrace) channels of naive CD8+ T cells obtained from Ezh2-g-KO mice. A representative cell that was tracked over time is indicated with a white arrowhead. The cell undergoing first and second division is marked with cyan and yellow arrowhe...
Data
Deletion of Ezh2 in Ezh2-c-KO CD8 T cells before and after in vitro stimulation. Naïve CD8+ T cells were isolated from spleen of WT or Ezh2-c-KO mice and stimulated with anti-CD3/CD28 in vitro. Cells were collected at 0, 24, and 96 h after stimulation and lysed in RIPA buffer. 10 mg lysate was separated on NuPAGE 4–12% Bis-Tris protein gel (Invitro...
Data
TUNNEL assay in Ezh2 deficient CD8+ T cells. WT or Ezh2-c-KO CD8+ naïve T cells were isolated and stimulated with anti-CD3 and anti-CD28 for 72 h in vitro. The cells were fixed with 1% (W/V) paraformaldehyde in PBS on ice for 15 min, and then resuspended in ice cold 70% ethanol, and incubated on ice for a minimum of 30 min. The fixed cells were lab...
Data
Live Imaging of naive CD8+ T cells of WT mice. Time lapse movie (2 fps) of overlaid DIC and Far Red (CellTrace) channels of naive CD8+ T cells obtained from WT mice. A representative cell that was tracked over time is indicated with a white arrowhead. The cell undergoing first and second division is marked with cyan and yellow arrowhead, respective...
Data
Live Imaging of naïve CD8+ T cells of Ezh2-g-KO mice. Time lapse movie (2 fps) of overlaid DIC and Far Red (CellTrace) channels of naive CD8+ T cells obtained from Ezh2-c-KO mice. A representative cell that was tracked over time is indicated with a white arrowhead. The cell undergoing first and second division is marked with cyan and yellow arrowhe...
Data
Tile scan profile of live cell imaging. WT, Ezh2-g-KO or Ezh2-c-KO CD8+ naïve T cells were labeled with CellTrace Far Red and stimulated with plate coated anti-CD3/CD28 (see Materials and Methods for details). The representative tile scan profile shows the complete imaging area of the chamber of interest in the silicone micro-insert. The edge effec...
Article
Full-text available
Influenza A virus (IAV) causes an acute infection in humans that is normally eliminated by CD8+ cytotoxic T lymphocytes. Individuals expressing the major histocompatibility complex (MHC) class I molecule HLA-A2 produce cytotoxic T lymphocytes bearing T cell receptors (TCRs) that recognize the immunodominant IAV epitope GILGFVFTL (GIL). Most GIL-spe...
Article
Full-text available
A number of biological parameters have been cited as hallmarks of immune aging. However, it is not clear whether these multiple biological changes are the result of common underlying aging processes and follow correlated trajectories, or whether the patterns of change for multiple parameters vary across individuals and reflect heterogeneity in the...
Article
A diverse TCR repertoire is considered as an essential property of T cell immunity to efficiently contain and eliminate viral invasion. However, limited information is available regarding the characteristics of TCR repertoire to a defined viral antigen peptide in human. Here, we report a comprehensive analysis of CD8 TCR repertoires, consensus bind...
Article
The activity of telomerase is regulated at multiple levels of the reverse transcriptase (hTERT) subunit. In T cells, it is well documented that telomerase activity is not detected in resting cells while it is high in activated cells. However, it is unclear whether full-length (FL) hTERT mRNA and AS products (ASPs) are expressed in resting T cells a...
Article
Full-text available
A diverse T cell receptor (TCR) repertoire is essential for controlling viral infections. However, information about TCR repertoires to defined viral antigens is limited. We performed a comprehensive analysis of CD8⁺ TCR repertoires for two dominant viral epitopes: pp65495–503 (NLV) of cytomegalovirus and M158–66 (GIL) of influenza A virus. The hig...
Article
Full-text available
Background Alterations in the number and composition of lymphocytes and their subsets in blood are considered a hallmark of immune system aging. However, it is unknown whether the rates of change of lymphocytes are stable or change with age, or whether the inter-individual variations of lymphocyte composition are stable over time or undergo differe...
Article
Accumulated DNA damage in hematopoietic stem cells is a primary mechanism of aging-associated dysfunction in human hematopoiesis. About 70 years ago, atomic-bomb (A-bomb) radiation induced DNA damage and functional decreases in the hematopoietic system of A-bomb survivors in a radiation dose-dependent manner. The peripheral blood cell populations t...
Article
CD8 T cells play a vital role in the immune response to viral infection. Diversity of the T cell antigen receptor (TCR) is believed to be essential for the host to survive in this microorganism-rich world. However, there is limited information regarding the characteristics of the TCR repertoire to defined viral antigens in humans. Here, we report a...
Article
Full-text available
Ionizing radiation (IR) is a major source of cellular damage and the immediate cellular response to IR has been well characterized. But the long-term impact of IR on cell function and its relationship with aging are not known. Here, we examined the IR effects on telomere length and other biomarkers 50 to 68 years post-exposure (two time points per...
Article
Full-text available
Cytomegalovirus (CMV) is a ubiquitous and persistent human pathogen that is kept in check by CD8+ cytotoxic T lymphocytes (CTLs). Individuals expressing the major histocompatibility complex (MHC) class I molecule HLA-A2 produce CTLs bearing T cell receptors (TCRs) that recognize the immunodominant CMV epitope NLVPMVATV (NLV). The NLV-specific T cel...
Article
The TCR repertoire serves as a reservoir of TCRs for recognizing all potential pathogens. Two major types of T cells, CD4(+) and CD8(+), that use the same genetic elements and process to generate a functional TCR differ in their recognition of peptide bound to MHC class II and I, respectively. However, it is currently unclear to what extent the TCR...
Article
Ezh2 catalyzes trimethylation of H3K27 and regulates transcriptional repression. It plays a vital role during stem cell development and cell differentiation. Although it is well documented that epigenetic changes regulate gene expression, the epigenetic mechanism during CD8 T cell differentiation are not fully understood. Here, we assessed the role...
Article
Background: Telomeres provide a key mechanism for protecting the integrity of chromosomes and their attrition after cell division and during aging are evident in lymphocytes. However, the significance of telomere shortening in age-associated decline of immune function is unknown. Methods: We selected 22 HLA-A2-positive healthy older adults who h...
Article
Telomeres are essential in maintaining chromosome integrity and in controlling cellular replication. Attrition of telomere length in peripheral blood mononuclear cells (PBMCs) with age is well documented from cross-sectional studies. But the actual in vivo changes in telomere lengths and its relationship with the contributing factors within the ind...
Article
Background: Norepinephrine (NE) is one of the primary catecholamines of the sympathetic nervous system released during a stress response and plays an important role in modulating immune function. NE binds to the adrenergic receptors on immune cells, including T cells, resulting in either suppressed or enhanced function depending on the type of cel...
Article
Full-text available
Chemokines play a pivotal role in regulating the immune response through a tightly controlled expression. Elevated levels of inflammatory chemokines commonly occur with aging but the mechanism underlying this age-associated change is not fully understood. Here, we report the role of microRNA-125b (miR-125b) in regulating inflammatory CC chemokine 4...
Article
Considering the commonality of chronic stress in today’s society, and vital role of the immune system in overall health, it is important to understand the molecular mechanisms by which stress interferes with immune function. In vitro studies have shown one stress hormone, norepinephrine (NE), decreases functionality and proliferation of immune cell...
Article
The T cell receptor (TCR) repertoire (diversity and distribution) is a vital parameter of the overall function of T cells. Reduction of TCR diversity and alteration of TCR distribution is believed to occur with age and acts as a major contributor for age-associated decline of immune function. However, neither the actual size of the TCR repertoire n...
Article
Chronic exposure to stress has detrimental effects on the adaptive immune response. Studies in vitro show that exposure of norepinephrine (NE), a stress hormone, decreases proliferation and functionality of T cells. T cells consist of several different types of cells and each of them serves distinct functions during an immune response. It is unknow...
Article
Genes containing both histone methylation H3K4me3 and H3K27me3 markers at the promoter are so called bivalent genes that have been implicated in stem cell differentiation and function. Our previous study identified several dozen bivalent genes in memory CD8 T cells (central memory, TCM and effector memory, TEM). But the role of bivalent genes in CD...
Article
The competency of antigen specific (Ag+) lymphocytes plays a critical role in the outcome of an adaptive immune response during an infection. Although the precursor frequency of Ag+ T cells often serves as an indicator, the evaluation of the proliferative capacity of Ag+ T cells of healthy humans to known viral antigens is limited. Here, we compare...
Article
Reactive oxygen species (ROS) play an important role in cell-mediated immune responses, although overproduction and excessive accumulation of ROS may also enhance risks of inflammation-related diseases. To address these concerns, we have developed an assay system to determine ROS (H2O2 and O2.-) levels in blood cells to investigate the effects age...
Article
Age carries a detrimental impact on T cell function. In the past decade, analyses of the genome-scale transcriptional changes of T cells during aging have yielded a large amount of data and provided a global view of gene expression changes in T cells from aged hosts as well as subsets of T cells accumulated with age. Here, we aim to review the chan...
Article
Full-text available
The ability of T-cells to respond to foreign antigens and to appropriately regulate this response is crucial for maintaining immune homeostasis. Using combinatorial peptide libraries, we functionally measured broad T-cell reactivity and observed impaired reactivity in established models of T-cell receptor repertoire restriction and in previously un...
Article
The competency of antigen specific (Ag+) lymphocytes plays a critical role in the adaptive immune response. However, little is known about the differences in the competency of Ag+ T cells against different viruses. Here, we compared the CD8 T cell responses of 23 healthy adults to CMV (pp65) or Flu (M1) peptides using an in vitro artificial antigen...
Article
Full-text available
Age-associated decline of immune function is believed to be mainly due to alterations of immune cells. However, longitudinal changes of human immune cells with age have not yet been adequately addressed. To test the hypothesis that regeneration of lymphocytes and monocytes is robust throughout most of adult life until advanced age, we examined six...
Article
Cellular and Molecular Immunology aims to report the dynamic progress being made in China and abroad in immunological research, and welcomes high-quality Research Articles, Reviews and Brief Reports across a broad range of topics including, but not limited to, clinical immunology, comparative immunology, immunobiology, immunogenetics, immunological...
Article
Telomeres are essential for the integrity of chromosomes and for cellular replication. Attrition of telomeres occurs during DNA replication owing to the inability of conventional DNA polymerase to replicate chromosomal termini and the insufficient compensation for telomere loss by telomerase, an enzyme that synthesizes telomeric DNA. A number of ge...