Homeodomain-only protein suppresses proliferation and contributes to differentiation- and age-related reduced CD8 T cell expansion.

T cell activation is a tightly controlled process involving both positive and negative regulators. The precise mechanisms governing the negative regulators in T cell proliferation remain incompletely understood. Here, we report that homeodomain-only protein (HOPX), a homeodomain-containing protein, and its most abundant isoform , negatively regulate activation-induced proliferation of human T cells.

Long-Term Dysfunction of Taste Papillae in SARS-CoV-2.

Background: We sought to determine whether ongoing taste disturbance in the postacute sequelae of coronavirus disease 2019 period is associated with persistent virus in primary taste tissue.

Methods: We performed fungiform papillae biopsies on 16 patients who reported taste disturbance lasting more than 6 weeks after molecularly determined severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Then, on multiple occasions, we rebiopsied 10 of those patients who still had taste complaints for at least 6 months postinfection.

A Phase I/II Clinical Trial of Intradermal, Controllable Self-Replicating Ribonucleic Acid Vaccine EXG-5003 against SARS-CoV-2.

mRNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have played a key role in reducing morbidity and mortality from coronavirus disease 2019 (COVID-19). We conducted a double-blind, placebo-controlled phase I/II trial to evaluate the safety, tolerability, and immunogenicity of EXG-5003, a two-dose, controllable self-replicating RNA vaccine against SARS-CoV-2. EXG-5003 encodes the receptor binding domain (RBD) of SARS-CoV-2 and was administered intradermally without lipid nanoparticles (LNPs).

SARS-CoV-2 infection establishes a stable and age-independent CD8 T cell response against a dominant nucleocapsid epitope using restricted T cell receptors.

The resolution of SARS-CoV-2 replication hinges on cell-mediated immunity, wherein CD8 T cells play a vital role. Nonetheless, the characterization of the specificity and TCR composition of CD8 T cells targeting non-spike protein of SARS-CoV-2 before and after infection remains incomplete. Here, we analyzed CD8 T cells recognizing six epitopes from the SARS-CoV-2 nucleocapsid (N) protein and found that SARS-CoV-2 infection slightly increased the frequencies of N-recognizing CD8 T cells but significantly enhanced activation-induced proliferation compared to that of the uninfected donors.

Epigenetic signature of human immune aging in the GESTALT study.

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 (naive B, naive CD4 and CD8 T cells, granulocytes, monocytes, and NK cells) collected from healthy individuals interspersed over a wide age range.

Numbers and odds: TCR repertoire size and its age changes impacting on T cell functions.

A vast array of αβ T cell receptors (TCRs) is generated during T cell development in the thymus through V(D)J recombination, which involves the rearrangement of multiple V, D, and J genes and the pairing of α and β chains. These diverse TCRs provide protection to the human body against a multitude of foreign pathogens and internal cancer cells. The entirety of TCRs present in an individual's T cells is referred to as the TCR repertoire.

Transcriptome-based measurement of CD8 T cell age and its applications.

The ability of T cells to undergo robust cell division in response to antigenic stimulation is essential for competent T cell function. However, this ability is reduced with aging and contributes to increased susceptibility to infectious diseases, cancers, and other diseases among older adults. To better understand T cell aging, improved measurements of age-related cellular changes in T cells are necessary.

Association of common infections with cognitive performance in the Baltimore Epidemiologic Catchment Area study follow-up.

Introduction: Growing evidence suggests that some common infections are causally associated with cognitive impairment; however, less is known about the burden of multiple infections.

Methods: We investigated the cross-sectional association of positive antibody tests for herpes simplex virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), and Toxoplasma gondii (TOX) with Mini-Mental State Examination (MMSE) and delayed verbal recall performance in 575 adults aged 41-97 from the Baltimore Epidemiologic Catchment Area Study.

Results: In multivariable-adjusted zero-inflated Poisson (ZIP) regression models, positive antibody tests for CMV (p = .

Controllable self-replicating RNA vaccine delivered intradermally elicits predominantly cellular immunity.

Intradermal delivery of self-replicating RNA (srRNA) is a promising vaccine platform. We have developed an srRNA that functions optimally at around 33°C (skin temperature) and is inactivated at or above 37°C (core body temperature) as a safety switch. This temperature-controllable srRNA (c-srRNA), when tested as an intradermal vaccine against SARS-CoV-2, functions when injected naked without lipid nanoparticles.

Lysine methyltransferase Kmt2d regulates naive CD8 T cell activation-induced survival.

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 modulating Foxp3 gene expression. Here we report a role of Kmt2d in naïve CD8 T cell generation and survival. In the absence of , the number of CD8 T cells, particularly naïve CD8 T cells (CD62L/CD44), in spleen was greatly decreased and activation-related death significantly increased from CD4cre (KO) compared to CD4cre (WT) mice.

Cytomegalovirus infection reduced CD70 expression, signaling and expansion of viral specific memory CD8 T cells in healthy human adults.

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 CMV epitope (pp65, NLV) and an influenza A virus (IAV) epitope (M1, GIL) from the same young and middle-aged healthy adults with serum positive for anti-CMV IgG.

Controllable self-replicating RNA vaccine delivered intradermally elicits predominantly cellular immunity.

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- c ontrollable srRNA (c-srRNA), when tested as an intradermal vaccine against SARS-CoV-2, functions when injected naked without lipid nanoparticles.

Heterogeneity and transcriptome changes of human CD8 T cells across nine decades of life.

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 subpopulations of CD8 T cells and their dynamic changes with age are identified.

Longitudinal analysis reveals age-related changes in the T cell receptor repertoire of human T cell subsets.

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 of the human blood TCRα and TCRβ repertoire of CD4+ and CD8+ T cell subsets using a unique molecular identifier-based (UMI-based) RNA-seq method.

DNA methylation signatures reveal that distinct combinations of transcription factors specify human immune cell epigenetic identity.

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 epigenetic and transcriptomic patterns. Sites of lineage-specific hypomethylation were associated with distinct combinations of transcription factors in each cell type.

Validation of the effectiveness of SARS-CoV-2 vaccines in older adults in "real-world" settings.

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 emerging variants may be lower. Adoptive immunotherapy with neutralizing mAb may offer an alternative for poor vaccine responders, while the mechanisms underlying failure to respond are still unclear.

Lipid Microbubble-Conjugated Anti-CD3 and Anti-CD28 Antibodies (Microbubble-Based Human T Cell Activator) Offer Superior Long-Term Expansion of Human Naive T Cells In Vitro.

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 human primary T cells in vitro. In this study, we report that an application using anti-CD3 and anti-CD28 Abs conjugated on lipid microbubbles (microbubble-based human T cell activator [MB-TCA]) to stimulate primary human naive T cells resulted in expansion superior to D-TCA.

Can an effective SARS-CoV-2 vaccine be developed for the older population?

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 conditions which demand a full understanding and leveraging of knowledge of the differences between immunity in young and old people. Consequently, we welcome papers addressing any issues relevant to immunity and ageing in the context of SARS-CoV-2, and will endeavour to fast-track peer-review.

Sex differences in the association between antinuclear antibody positivity with diabetes and multimorbidity in older adults: Results from the Baltimore Longitudinal Study of Aging.

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. Immune system differences by sex may further result in sex-specific susceptibility to morbidity.

TCR Repertoires of Thymic Conventional and Regulatory T Cells: Identification and Characterization of Both Unique and Shared TCR Sequences.

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.

Telomere length and cognitive function: Differential patterns across sociodemographic groups.

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.

Expression and regulation of telomerase in human T cell differentiation, activation, aging and diseases.

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 proliferation in response to engagement of the T cell antigen receptor (TCR) or exposure to homeostatic cytokines.