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The progressive impairment of immunity to pathogens and vaccines with aging is a significant public health problem as the world population shifts to an increased percentage of older adults (> 65). We have previously demonstrated that cells obtained from older volunteers have delayed and defective induction of type I interferons and T cell and B cell helper cytokines in response to TLR ligands when compared to those from adult subjects. However, the underlying intracellular mechanisms are not well described. Herein, we studied two critical pathways important in the production of type I interferon (IFN), the interferon response factor 7 (pIRF7), and TANK-binding kinase (pTBK-1). We show a decrease in pIRF7 and pTBK-1 in cross-priming dendritic cells (cDC1s), CD4+T cell priming DCs (cDC2s), and CD14dimCD16+vascular patrolling monocytes from older adults (n = 11) following stimulation with pathway-specific agonists in comparison with young individuals (n = 11). The decrease in these key antiviral pathway proteins correlates with decreased phagocytosis, suggesting impaired function in Overall, our findings describe molecular mechanisms which explain the innate functional impairment in older adults and thus could inform us of novel approaches to restore these defects.Graphical abstract

Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have shown high efficacy, but immunocompromised participants were excluded from controlled clinical trials. In this study, we compared immune responses to the BNT162b2 mRNA Coronavirus Disease 2019 vaccine in patients with solid tumors (n = 53) who were on active cytotoxic anti-cancer therapy to a control cohort of participants without cancer (n = 50). Neutralizing antibodies were detected in 67% of patients with cancer after the first immunization, followed by a threefold increase in median titers after the second dose. Similar patterns were observed for spike protein-specific serum antibodies and T cells, but the magnitude of each of these responses was diminished relative to the control cohort. In most patients with cancer, we detected spike receptor-binding domain and other S1-specific memory B cell subsets as potential predictors of anamnestic responses to additional immunizations. We therefore initiated a phase 1 trial for 20 cancer cohort participants of a third vaccine dose of BNT162b2 ( NCT04936997 ); primary outcomes were immune responses, with a secondary outcome of safety. At 1 week after a third immunization, 16 participants demonstrated a median threefold increase in neutralizing antibody responses, but no improvement was observed in T cell responses. Adverse events were mild. These results suggest that a third dose of BNT162b2 is safe, improves humoral immunity against SARS-CoV-2 and could be immunologically beneficial for patients with cancer on active chemotherapy. After two doses of the BNT162b2 vaccine, virus-specific antibodies and T cells were reduced in patients with solid tumors as compared to individuals without cancer, but neutralizing antibodies increased in most patients who received a third vaccine dose.

Naive T (Tn) cells require two homeostatic signals for long-term survival: tonic T cell receptor:self-peptide–MHC contact and IL-7 stimulation. However, how microbial exposure impacts Tn homeostasis is still unclear. Here we show that infections can lead to the expansion of a subpopulation of long-lived, Ly6C+ CD8+ Tn cells with accelerated effector function. Mechanistically, mono-infection with West Nile virus transiently, and polymicrobial exposure persistently, enhances Ly6C expression selectively on CD5hiCD8+ cells, which in the case of polyinfection translates into a numerical CD8+ Tn cell increase in the lymph nodes. This conversion and expansion of Ly6C+ Tn cells depends on IFN-I, which upregulates MHC class I expression and enhances tonic TCR signaling in differentiating Tn cells. Moreover, for Ly6C+CD8+ Tn cells, IFN-I-mediated signals optimize their homing to secondary sites, extend their lifespan, and enhance their effector differentiation and antibacterial function, particularly for low-affinity clones. Our results thus uncover significant regulation of Tn homeostasis and function via infection-driven IFN-I, with potential implications for immunotherapy. Infections induce activation of naive T cells for protective immunity, but insights for this host-pathogen crosstalk are still missing. Here the authors show that infection-induced type I interferon (IFN-I) signaling promote the differentiation, expansion and functional maturation of naive CD8 T cells, particularly for low affinity clones, to enhance anti-microbial immunity.

SUMMARYHIV-positive patients whose viral loads are successfully controlled by active antiretroviral therapy (ART) show no clinical signs of AIDS. However, their lifespan is shorter compared to individuals with no HIV infection and they prematurely exhibit a multitude of chronic diseases typically associated with advanced age. It was hypothesized that immune system aging may correlate with, and provide useful biomarkers for, this premature loss of healthspan in HIV+ subjects. Here, we tested whether the immune correlates of aging, including cell numbers and phenotypes, inflammatory status and control of human cytomegalovirus (hCMV) in HIV-positive subjects on long-term successful ART (HIV+) may reveal increased “immunological age” compared to healthy, age-matched cohort (HC) in participants between 50 and 69 years of age. Specifically, we expected that younger HIV+ subjects may immunologically resemble older individuals without HIV. We found no evidence to support this hypothesis. While T cells from HIV+ participants displayed different expression of several differentiation and/or inhibitory/exhaustion markers in different T cell subpopulations, aging by a decade did not pronounce these changes. Similarly, while the HIV+ participants exhibited higher T cell responses and elevated inflammatory marker levels in plasma, indicative of chronic inflammation, this trait was not age-sensitive. We did find differences in immune control of hCMV, and, more importantly, a sustained elevation of sCD14 and of proinflammatory CD4 and CD8 T cell responses across age groups, pointing towards uncontrolled inflammation as a factor in reduced healthspan in successfully treated older HIV+ patients.

While whole-body irradiation (WBI) can induce some hallmarks of immune aging, (re)activation of persistent microbial infection also occurs following WBI and may contribute to immune effects of WBI over the lifespan. To test this hypothesis in a model relevant to human immune aging, we examined separate and joint effects of lifelong latent murine cytomegalovirus (MCMV) and of early-life WBI over the course of the lifespan. In late life, we then measured the response to a West Nile virus (WNV) live attenuated vaccine, and lethal WNV challenge subsequent to vaccination. We recently published that a single dose of non-lethal WBI in youth, on its own, was not sufficient to accelerate aging of the murine immune system, despite widespread DNA damage and repopulation stress in hematopoietic cells. However, 4Gy sub-lethal WBI caused manifest reactivation of MCMV. Following vaccination and challenge with WNV in the old age, MCMV-infected animals experiencing 4Gy, but not lower, dose of sub-lethal WBI in youth had reduced survival. By contrast, old irradiated mice lacking MCMV and MCMV-infected, but not irradiated, mice were both protected to the same high level as the old non-irradiated, uninfected controls. Analysis of the quality and quantity of anti-WNV immunity showed that higher mortality in MCMV-positive WBI mice correlated with increased levels of MCMV-specific immune activation during WNV challenge. Moreover, we demonstrate that infection, including that by WNV, led to MCMV reactivation. Our data suggest that MCMV reactivation may be an important determinant of increased late-life mortality following early-life irradiation and late-life acute infection.

New infections in general, and new viral infections amongst them, represent a serious challenge to an older organism. This review discusses the age-related alterations in responsiveness to infection from the standpoint of virus:host relationship and the host physiological whole-organism and specific immune response to the virus. Changes with age in the innate and adaptive immune system homeostasis and function are reviewed briefly. This is followed by a review of specific alterations and defects in the response of older organisms (chiefly mice and humans) to acute (particularly emerging and re-emerging) viral infections, with a very brief summary of the response to latent persistent infections. Finally, we provide a brief summary of the perspectives for possible interventions to enhance antiviral immunity.

Several studies have demonstrated that the SARS-CoV-2 variant-of-concern B.1.1.529 (Omicron) exhibits a high degree of escape from Ab neutralization. Therefore, it is critical to determine how well the second line of adaptive immunity, T cell memory, performs against Omicron. To this purpose, we analyzed a human cohort (n = 327 subjects) of two- or three-dose mRNA vaccine recipients and COVID-19 postinfection subjects. We report that T cell responses against Omicron were largely preserved. IFN-γ–producing T cell responses remained equivalent to the response against the ancestral strain (WA1/2020), with some (∼20%) loss in IL-2 single or IL-2+IFN-γ+ polyfunctional responses. Three-dose vaccinated participants had similar responses to Omicron relative to post–COVID-19 participants and exhibited responses significantly higher than those receiving two mRNA vaccine doses. These results provide further evidence that a three-dose vaccine regimen benefits the induction of optimal functional T cell immune memory.

Older humans and animals often exhibit reduced immune responses to infection and vaccination, and this often directly correlates to the numbers and frequency of naive T (Tn) cells. We found such a correlation between reduced numbers of blood CD8+ Tn cells and severe clinical outcomes of West Nile virus (WNV) in both humans naturally exposed to, and mice experimentally infected with, WNV. To examine possible causality, we sought to increase the number of CD8 Tn cells by treating C57BL/6 mice with IL-7 complexes (IL-7C, anti-IL-7 mAb bound to IL-7), shown previously to efficiently increase peripheral T-cell numbers by homeostatic proliferation. T cells underwent robust expansion following IL-7C administration to old mice increasing the number of total T cells (fourfold) and NS4b:H-2D

Emergence of the SARS-CoV-2 variant-of-concern (VOC) B.1.1.529 (Omicron) in late 2021 has raised alarm among scientific and health care communities due to a surprisingly large number of mutations in its spike protein. Public health surveillance indicates that the Omicron variant is significantly more contagious than the previously dominant VOC, B.1.617.2 (Delta). Several early reports demonstrated that Omicron exhibits a higher degree (∼10-30-fold) of escape from antibody neutralization compared to earlier lineage variants. Therefore, it is critical to determine how well the second line of adaptive immunity, T cell memory, performs against Omicron in people following COVID-19 infection and/or vaccination. To that purpose, we analyzed a cohort (n=345 subjects) of two-or three-dose messenger RNA (mRNA) vaccine recipients and COVID-19 post infection subjects (including those receiving 2 doses of mRNA vaccine after infection), recruited to the CDC-sponsored AZ HEROES research study, alongside 32 pre-pandemic control samples. We report that T cell responses against Omicron spike peptides were largely preserved in all cohorts with established immune memory. IFN-γ producing T cell responses remained equivalent to the response against the ancestral strain (WA1/2020), with some (

Saliva specimens have drawn interest for diagnosing respiratory viral infections due to their ease of collection and decreased risk to healthcare providers. However, rapid and sensitive immunoassays have not yet been satisfactorily demonstrated for such specimens due to their viscosity and low viral loads. Using paper microfluidic chips and a smartphone-based fluorescence microscope, we developed a highly sensitive, low-cost immunofluorescence particulometric SARS-CoV-2 assay from clinical saline gargle samples. We demonstrated the limit of detection of 10 ag/μL. With easy-to-collect saline gargle samples, our clinical sensitivity, specificity, and accuracy were 100%, 86%, and 93%, respectively, for n = 27 human subjects with n = 13 RT-qPCR positives.

The pathogenicity of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been attributed to its ability to enter through the membrane-bound angiotensin-converting enzyme 2 (ACE2) receptor. Therefore, it has been heavily speculated that angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy may modulate SARS-CoV-2 infection. In this study, exposure of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and human endothelial cells (hECs) to SARS-CoV-2 identified significant differences in protein coding genes involved in immunity, viral response, and cardiomyocyte/endothelial structure. Specifically, transcriptome changes were identified in the tumor necrosis factor (TNF), interferon α/β, and mitogen-activated protein kinase (MAPK) (hPSC-CMs) as well as nuclear factor kappa-B (NF-κB) (hECs) signaling pathways. However, pre-treatment of hPSC-CMs or hECs with two widely prescribed antihypertensive medications, losartan and lisinopril, did not affect the susceptibility of either cell type to SARS-CoV-2 infection. These findings demonstrate the toxic effects of SARS-CoV-2 in hPSC-CMs/hECs and, taken together with newly emerging multicenter trials, suggest that antihypertensive drug treatment alone does not alter SARS-CoV-2 infection.

Cellular changes in the adaptive immune system accompanies the aging process and contributes to an age-related immune phenotype (ARIP) characterized by decrease in naïve T (TN) cells and increase in memory T (TM) cells. However, a population level marker of ARIP associated with biological aging and age-related chronic conditions has not been evaluated previously. We developed two ARIP measures based on well understood age related changes in T cell distribution: TN/ (TCM (Central Memory) + TEM (Effector Memory) + TEFF (Effector)) or TN/ TM in CD4+ and CD8+ T cells. We compared them with more commonly used ARIP measures such as CD4/CD8 ratio and CD8+ TN cells by evaluating associations with chronological age and phenotypic age using linear regression and association with multimorbidity using multinomial logistic regression. CD8+ TN and TN/TM had the strongest inverse association with chronological age (beta estimates: -3.41, -3.61; p-value< 0.0001). CD4+ TN/TM had the strongest inverse association with phenotypic age (beta estimate = -0.74; p-value < 0.0001) after adjustment for age, sex, race and CMV serostatus. CD4+ TN/TM was inversely associated with co-occurring chronic conditions (odds ratio for 2 conditions and 3 conditions vs. 0 conditions: 0.74 (95%CI: 0.63-0.86) and 0.75 (95% CI: 0.63-0.90), respectively) after adjustment for age, sex, race, CMV serostatus, smoking, and BMI. CD4+ TN/TM had a stronger association with phenotypic age and age-related morbidity compared to other ARIP measures. Future longitudinal studies can help us evaluate if CD4+ TN/TM can predict risk of aging related outcomes.

Older humans and animals often exhibit reduced immune responses to infection and vaccination, and this often directly correlates to the numbers and frequency of naïve T (Tn) cells. We found such a correlation between reduced numbers of blood CD8+ Tn cells and severe clinical outcomes of West Nile virus (WNV) in both humans naturally exposed to, and mice experimentally infected with, WNV.To examine possible causality, we sought to increase the number of CD8 Tn cells by treating C57BL/6 mice with IL-7 complexes (IL-7C, anti-IL-7 mAb bound to IL-7), shown previously to efficiently increase peripheral T cell numbers by homeostatic proliferation. T cells underwent robust expansion following IL-7C administration to old mice increasing the number of total T cells (>four-fold) and NS4b:H-2Db-restricted antigen-specific CD8 T cells (two-fold). This improved the numbers of NS4b-specific CD8 T cells detected at the peak of the response against WNV, but not survival of WNV challenge. IL-7C treated old animals also showed no improvement in WNV-specific effector immunity (neutralizing antibody and in vivo T cell cytotoxicity). To test quantitative limits to which CD8 Tn cell restoration could improve protective immunity, we transferred graded doses of Ag-specific precursors into old mice and showed that injection of 5,400 (but not of 1,800 or 600) adult naïve WNV-specific CD8 T cells significantly increased survival after WNV. These results set quantitative limits to the level of Tn reconstitution necessary to improve immune defense in older organisms and are discussed in light of targets of immune reconstitution.

Aging is associated with a reduced magnitude of primary immune responses to vaccination and constriction of immune receptor repertoire diversity. Clinical trials demonstrated high efficacy of mRNA based SARS-CoV-2 vaccines in older adults but concerns about virus variant escape have not been well addressed. We have conducted an in-depth analysis of humoral and cellular immunity against an early-pandemic viral isolate and compared that to the P.1. (Gamma) and B.1.617.2 (Delta) variants in 55 age cohorts of mRNA vaccine recipients. We have further measured neutralizing antibody titers for B.1.617.1 (Kappa) and B.1.595; a SARS-CoV-2 isolate bearing Spike mutation E484Q. As reported, robust immunity required the second dose of vaccine. Older vaccinees manifested robust cellular immunity against early-pandemic SARS-CoV-2 and more recent variants, which remained statistically comparable to the adult group. The older cohort had lower neutralizing capacity at the first time point following the second dose, but at later time points immunity was indistinguishable between them. While the duration of these immune responses remains to be determined over longer periods of time, these results provide reasons for optimism regarding vaccine protection of older adults against SARS-CoV-2 variants and inform thinking about boost vaccination with variant vaccines.eTOC summaryVaccine responses are often diminished with aging, but we found strong responses to SARS-CoV-2 in older adults following mRNA vaccination. T cell responses were not diminished when confronted by SARS-CoV-2 variants. Neutralizing Ab were reduced but not more than those in adults.Graphical AbstractCreated with BioRender.com

Aging is associated with a reduced magnitude of primary immune responses to vaccination. mRNA-based SARS-CoV-2 vaccines have shown efficacy in older adults but virus variant escape is still unclear. Here we analyze humoral and cellular immunity against an early-pandemic viral isolate and compare that to the P.1 (Gamma) and B.1.617.2 (Delta) variants in two cohorts (55 age) of mRNA vaccine recipients. We further measure neutralizing antibody titers for B.1.617.1 (Kappa) and B.1.595, with the latter SARS-CoV-2 isolate bearing the spike mutation E484Q. Robust humoral immunity is measured following second vaccination, and older vaccinees manifest cellular immunity comparable to the adult group against early-pandemic SARS-CoV-2 and more recent variants. More specifically, the older cohort has lower neutralizing capacity at 7-14 days following the second dose but equilibrates with the younger cohort after 2-3 months. While long-term vaccination responses remain to be determined, our results implicate vaccine-induced protection in older adults against SARS-CoV-2 variants and inform thinking about boost vaccination.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the third highly pathogenic coronavirus to emerge in the human population in last two decades. SARS-CoV-2 spread from Wuhan, China, across the globe, causing an unprecedented public healthcare crisis. The virus showed remarkable age dependent pathology, with symptoms resembling common cold in most adults and children while causing more severe respiratory distress and significant mortality in older and frail humans. Even before the SARS-CoV-2 outbreak infectious diseases represented one of the major causes of death of older adults. Loss of immune function and reduced protection from infectious agents with age - immunosenescence - is a result of complex mechanisms affecting production and maintenance of immune cells as well as the initiation, maintenance and termination of properly directed immune responses. Here we briefly discuss the current knowledge on how this process affects age-dependent outcomes of SARS-CoV-2 infection.

Though T-cell immunosenescence is a major risk factor for age-related diseases, susceptibility to infections, and responses to vaccines, differences in T-cell subset counts and representation by age and sex have not been determined for a large sample representative of the national population of the United States. We evaluated the counts of T-cell subsets including total, CD4+, and CD8+ T cells and their naïve (Tn), effector memory (Tem), and effector subsets, in the context of age, sex, and exposure to cytomegalovirus (CMV) infection among 8 848 Health and Retirement Study participants, a nationally representative study of adults older than 55 years. Total T cells (CD3+) and CD4+ cells declined markedly with age; CD8+ T cells declined somewhat less. While CD4+ T cell declines with age occurred for both CMV-seropositive and CMV-seronegative groups, total T cells and CD8+ cells were both substantially higher among the CMV-seropositive group. Numbers of Tn CD4+ and CD8+ cells were strongly and inversely related to age, were better conserved among women, and were independent of CMV seropositivity. By contrast, accumulation of the CD8+ and CD4+ Tem and effector subsets was CMV-associated. This is the first study to provide counts of T-cell subsets by age and sex in a national sample of US adults older than the age of 55 years. Understanding T-cell changes with age and sex is an important first step in determining strategies to reduce its impact on age-related diseases and susceptibility to infection.

Cytomegalovirus (CMV) is one of the most ubiquitous human latent persistent viruses. While this virus can be highly harmful and even deadly to the developing fetus and to severely immunocompromised individuals, it appears to be overtly well tolerated and compatible with long life in the vast majority of infected individuals. However, several epidemiological studies have linked CMV to metabolic disturbances, obesity, diabetes, cardiovascular diseases, frailty, and other chronic diseases. CMV was also proposed to be a potentially causal factor for some manifestations of immune aging, including an accumulation of highly differentiated T cells and potential increase in subclinical systemic inflammation. Given that many of the earlier mentioned issues have not been conclusively and mechanistically settled, this chapter will discuss our current understanding of the impact of CMV on the aging of the immune system and of the whole organism.

We conducted a serological study to define correlates of immunity against SARS-CoV-2. Relative to mild COVID-19 cases, individuals with severe disease exhibited elevated virus-neutralizing titers and antibodies against nucleocapsid (N) and the receptor binding domain (RBD) of spike protein. Age and sex played lesser roles. All cases, including asymptomatic individuals, seroconverted by 2 weeks post-PCR confirmation. Spike RBD and S2 and neutralizing antibodies remained detectable through 5-7 months post-onset, whereas α-N titers diminished. Testing of 5882 members of the local community revealed only 1 sample with seroreactivity to both RBD and S2 that lacked neutralizing antibodies. This fidelity could not be achieved with either RBD or S2 alone. Thus, inclusion of multiple independent assays improved the accuracy of antibody tests in low seroprevalence communities and revealed differences in antibody kinetics depending on the antigen. We conclude that neutralizing antibodies are stably produced for at least 5-7 months after SARS-CoV-2 infection., Graphical Abstract, Highlights • Using independent SARS-CoV-2 antigens improves specificity of serological assays • Neutralizing and spike-specific antibody production persists for at least 5-7 months • Nucleocapsid antibodies frequently become undetectable by 5-7 months • Antibody production is higher in severe disease relative to mild cases, Serological assays for SARS-CoV-2 exposures are challenging due to poor positive predictive values. Ripperger et al. show that combinatorial use of spike receptor binding domain and S2 eliminates almost all false positives. This serological assay is used to show durable antibody production for at least 5-7 months after infection.

We conducted an extensive serological study to quantify population-level exposure and define correlates of immunity against SARS-CoV-2. We found that relative to mild COVID-19 cases, individuals with severe disease exhibited elevated authentic virus-neutralizing titers and antibody levels against nucleocapsid (N) and the receptor binding domain (RBD) and the S2 region of spike protein. Unlike disease severity, age and sex played lesser roles in serological responses. All cases, including asymptomatic individuals, seroconverted by 2 weeks post-PCR confirmation. RBD- and S2-specific and neutralizing antibody titers remained elevated and stable for at least 2-3 months post-onset, whereas those against N were more variable with rapid declines in many samples. Testing of 5882 self-recruited members of the local community demonstrated that 1.24% of individuals showed antibody reactivity to RBD. However, 18% (13/73) of these putative seropositive samples failed to neutralize authentic SARS-CoV-2 virus. Each of the neutralizing, but only 1 of the non-neutralizing samples, also displayed potent reactivity to S2. Thus, inclusion of multiple independent assays markedly improved the accuracy of antibody tests in low seroprevalence communities and revealed differences in antibody kinetics depending on the viral antigen. In contrast to other reports, we conclude that immunity is durable for at least several months after SARS-CoV-2 infection.

The scale of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has thrust immunology into the public spotlight in unprecedented ways. In this article, which is part opinion piece and part review, we argue that the normal cadence by which we discuss science with our colleagues failed to properly convey likelihoods of the immune response to SARS-CoV-2 to the public and the media. As a result, biologically implausible outcomes were given equal weight as the principles set by decades of viral immunology. Unsurprisingly, questionable results and alarmist news media articles have filled the void. We suggest an emphasis on setting expectations based on prior findings while avoiding the overused approach of assuming nothing. After reviewing Ab-mediated immunity after coronavirus and other acute viral infections, we posit that, with few exceptions, the development of protective humoral immunity of more than a year is the norm. Immunity to SARS-CoV-2 is likely to follow the same pattern.

The complexity of host-associated microbial ecosystems requires host-specific reference catalogs to survey the functions and diversity of these communities. We generate a comprehensive resource, the integrated mouse gut metagenome catalog (iMGMC), comprising 4.6 million unique genes and 660 metagenome-assembled genomes (MAGs), many (485 MAGs, 73%) of which are linked to reconstructed full-length 16S rRNA gene sequences. iMGMC enables unprecedented coverage and taxonomic resolution of the mouse gut microbiota; i.e., more than 92% of MAGs lack species-level representatives in public repositories (

SARS, a new type of respiratory disease caused by SARS-CoV, was identified in 2003 with significant levels of morbidity and mortality. The recent pandemic of COVID-19, caused by SARS-CoV-2, has generated even greater extents of morbidity and mortality across the entire world. Both SARS-CoV and SARS-CoV-2 spreads through the air in the form of droplets and potentially smaller droplets (aerosols) via exhaling, coughing, and sneezing. Direct detection from such airborne droplets would be ideal for protecting general public from potential exposure before they infect individuals. However, the number of viruses in such droplets and aerosols is too low to be detected directly. A separate air sampler and enough collection time (several hours) are necessary to capture a sufficient number of viruses. In this work, we have demonstrated the direct capture of the airborne droplets on the paper microfluidic chip without the need for any other equipment. 10% human saliva samples were spiked with the known concentration of SARS-CoV-2 and sprayed to generate liquid droplets and aerosols into the air. Antibody-conjugated submicron particle suspension is then added to the paper channel, and a smartphone-based fluorescence microscope isolated and counted the immunoagglutinated particles on the paper chip. The total capture-to-assay time was

The objective of this study was to evaluate effects of whole body radiation exposure early in life on influenza vaccination immune responses much later in life. A total of 292 volunteers recruited from the cohort members of ongoing Adult Health Study (AHS) of Japanese atomic bomb (A-bomb) survivors completed this observational study spanning two influenza seasons (2011-2012 and 2012-2013). Peripheral blood samples were collected prior to and three weeks after vaccination. Serum hemagglutination inhibition (HAI) antibody titers were measured as well as concentrations of 25 cytokines and chemokines in culture supernatant from peripheral blood mononuclear cells, with and without in vitro stimulation with influenza vaccine. We found that influenza vaccination modestly enhanced serum HAI titers in this unique cohort of elderly subjects, with seroprotection ranging from 18 to 48% for specific antigen/season combinations. Twelve percent of subjects were seroprotected against all three vaccine antigens post-vaccination. Males were generally more likely to be seroprotected for one or more antigens post-vaccination, with no differences in vaccine responses based on age at vaccination or radiation exposure in early life. These results show that early life exposure to ionizing radiation does not prevent responses of elderly A-bomb survivors to seasonal influenza vaccine.

Calorie restriction (CR) without malnutrition increases life span and health span in multiple model organisms. In non-human and human primates, CR causes changes that protect against several age-related pathologies, reduces inflammation, and preserves or improves cell-mediated immunity. However, CR has also been shown to exhibit adverse effects on certain organs and systems, including the immune system, and to impact genetically different organisms of the same species differentially. Alternately, short periods of fasting followed by refeeding may result in the proliferation of bone marrow stem cells, suggesting a potential rejuvenation effect that could impact the hematopoietic compartment. However, the global consequences of CR followed by refeeding on the immune system have not been carefully investigated. Here, we show that individuals practicing long-term CR with adequate nutrition have markedly lower circulating levels of total leukocytes, neutrophils, lymphocytes, and monocytes. In 10-month-old mice, short-term CR lowered lymphocyte cellularity in multiple lymphoid tissues, but not in bone marrow, which appears to be a site of influx, or a “safe haven” for B, NK, and T cells during CR. Cellular loss and redistribution was reversed within the first week of refeeding. Based on BrdU incorporation and Ki67 expression assays, repopulating T cells exhibited high proliferation in the refeeding group following CR. Finally, we demonstrated that the thymus was not essential for T cell repopulation following refeeding. These findings are of potential relevance to strategies to rejuvenate the immune system in mammals and warrant further investigation.

Cytomegalovirus (CMV) is one of the most complex and most ubiquitous latent persistent viruses, with a considerable ability to evade and manipulate the immune system. Following an early-life infection, most immunocompetent humans spend several decades living with CMV, and, because the virus in these hosts does not cause manifest disease, CMV can be considered part of normal aging for more than half of humanity. However, there is accumulating evidence that CMV carriage is not a null event and that both potentially harmful and potentially beneficial outcomes emanate from the interaction of CMV with its mammalian hosts. This article provides an overview of the 6th International Workshop on CMV and Immunosenescence, highlighting the advances in the field made in the past two years, as related to CMV epidemiology/geroscience, CMV virology with an accent on latency, and CMV immune evasion and immune recognition of the virus and its antigens.

In response to infection with intracellular microorganisms, old mice mobilize decreased numbers of antigen-specific CD8 T cells with reduced expression of effector molecules and impaired cytolytic activity. Molecular mechanisms behind these defects and the cell-intrinsic (affecting naïve CD8 T cells themselves) vs. extrinsic, microenvironmental origin of such defects remain unclear. Using reciprocal transfer experiments of highly purified naïve T cells from adult and old transgenic OT-1 mice, we decisively show that the dominant effect is cell-extrinsic. Naïve adult OT-1 T cells failed to expand and terminally differentiate in the old organism infected with Listeria-OVA. This defect was preceded by blunted expression of the master transcription factor T-bet and impaired glycolytic switch when T cells are primed in the old organism. However, both old and adult naïve CD8 T cells proliferated and produced effector molecules to a similar extent when stimulated in vitro with polyclonal stimuli, as well as when transferred into adult recipients. Multiple inflammatory cytokines with direct effects on T cell effector differentiation were decreased in spleens of old animals, particularly IL-12 and IL-18. Of note, in vivo treatment of mice with IL-12 and IL-18 on days 4–6 of Listeria infection reconstituted cytotoxic T cell response of aged mice to the level of adult. Therefore, critical cytokine signals which are underproduced in the old priming environment can restore proper transcriptional programming of old naïve CD8 T cells and improve immune defense against intracellular microorganisms.

Cytomegalovirus (CMV) is a ubiquitous herpesvirus infecting most of the world’s population. CMV has been rigorously investigated for its impact on lifelong immunity and potential complications arising from lifelong infection. A rigorous adaptive immune response mounts during progression of CMV infection from acute to latent states. CD8 T cells, in large part, drive this response and have very clearly been demonstrated to take up residence in the salivary gland and lungs of infected mice during latency. However, the role of tissue resident CD8 T cells as an ongoing defense mechanism against CMV has not been studied in other anatomical locations. Therefore, we sought to identify additional locations of anti-CMV T cell residency and the physiological consequences of such a response. Through RT-qPCR we found that mouse CMV (mCMV) infected the visceral adipose tissue and that this resulted in an expansion of leukocytes in situ. We further found, through flow cytometry, that adipose tissue became enriched in cytotoxic CD8 T cells that are specific for mCMV antigens from day 7 post infection through the lifespan of an infected animal (> 450 days post infection) and that carry markers of tissue residence. Furthermore, we found that inflammatory cytokines are elevated alongside the expansion of CD8 T cells. Finally, we show a correlation between the inflammatory state of adipose tissue in response to mCMV infection and the development of hyperglycemia in mice. Overall, this study identifies adipose tissue as a location of viral infection leading to a sustained and lifelong adaptive immune response mediated by CD8 T cells that correlates with hyperglycemia. These data potentially provide a mechanistic link between metabolic syndrome and chronic infection., Author summary Mouse cytomegalovirus (mCMV) infection results in initial systemic viremia that is thereafter controlled by the adaptive immune system. Control is mediated in part by T cells that render the virus undetectable systemically, and latent in specific organs, including the lungs and salivary glands. It remains unclear how latent virus is controlled across tissues given the large pool of systemic mCMV-specific T cells. We explored mCMV control in the adipose tissue, whose cellular constituents are potentially susceptible to infection. We found that mCMV infects the adipose tissue during the acute phase, causing local inflammation and a lifelong mCMV-specific CD8 T cell immune response. The response consisted largely from non-recirculating, tissue-resident T cells. The infected adipose tissue showed signs of metabolic changes, that may potentially predispose the infected host to metabolic dysregulation as evidenced by hyperglycemia. Accumulation and persistence of mCMV specific non-circulating resident CD8 T cells (Trm) in adipose tissue reveal a likely generalized mechanism of mCMV tissue reservoir control by Trm cells and identify the adipose tissue as a persistent mCMV reservoir, with potential implications for metabolic health.

In both mice and humans, the CD8 T cell compartment is expanded with age in the presence of a cytomegalovirus (CMV) infection due to an absolute increase in the CD8+ T cell effector memory (T(EM)) cells. It has been hypothesized that in CMV+ subjects, such accumulated T(EM) cells could interfere with responses to new infection by competing for space/resources or could inhibit new responses by other, undefined, means. Here we present evidence against this hypothesis. We show that MCMV-specific CD8 T cells accumulate in blood and bone marrow, but not lymph nodes (frequent sites of immune response initiation), in either persistent lifelong CMV infection or following reactivation. Moreover, adoptive transfer of effector memory T cells from MCMV positive mice into naïve animals did not interfere with either humoral or cellular response to West Nile virus or Listeria monocytogenes infection in recipient mice. We conclude that MCMV infection is unlikely to inhibit new immune responses in old animals through direct interference of MCMV-specific CD8 T cells with the priming. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11357-019-00068-0) contains supplementary material, which is available to authorized users.

Aging is accompanied by significant defects in immunity and compromised responses to new, previously unencountered microbial pathogens. Most humans carry several persistent or latent viruses as they age, interacting with the host immune systems for years. In that context maybe the most studied persistent virus is Cytomegalovirus, infamous for its ability to recruit very large T cell responses which increase with age and to simultaneously evade elimination by the immune system. Here we will address how lifelong CMV infection and the immunological burden of its control might affect immune reactivity and health of the host over time.

Summary Ageing of the innate and adaptive immune system, collectively termed immune senescence, is a complex process. One method to understand the components of ageing involves dissociating the effects of ageing on the cells of the immune system, on the microenvironment in lymphoid organs and tissues where immune cells reside and on the circulating factors that interact with both immune cells and their microenvironment. Heterochronic parabiosis, a surgical union of two organisms of disparate ages, is ideal for this type of study, as it has the power to dissociate the age of the cell and the age of the microenvironment into which the cell resides or is migrating. So far, however, it has been used sparingly to study immune ageing. Here we review the limited literature on homeostatic innate immune cell trafficking in ageing in the absence of chronic inflammation. We also review our own recent data on trafficking of innate immune subsets between primary and secondary lymphoid organs in heterochronic parabiosis. We found no systemic bias in retention or acceptance of neutrophils, macrophages, dendritic cells or natural killer cells with ageing in primary and secondary lymphoid organs. We conclude that these four innate immune cell types migrate to and populate lymphoid organs (peripheral lymph nodes, spleen and bone marrow), regardless of their own age and of the age of lymphoid organs.

The number of naive T cells decreases and susceptibility to new microbial infections increases with age. Here we describe a previously unknown subset of phenotypically naive human CD8(+) T cells that rapidly secreted multiple cytokines in response to persistent viral antigens but differed transcriptionally from memory and effector T cells. The frequency of these CD8(+) T cells, called 'memory T cells with a naive phenotype' (TMNP cells), increased with age and after severe acute infection and inversely correlated with the residual capacity of the immune system to respond to new infections with age. CD8(+) TMNP cells represent a potential new target for the immunotherapy of persistent infections and should be accounted for and subtracted from the naive pool if truly naive T cells are needed to respond to antigens.

Summary Aging‐related decline in immunity is believed to be the main driver behind decreased vaccine efficacy and reduced resistance to infections in older adults. Unrepaired DNA damage is known to precipitate cellular senescence, which was hypothesized to be the underlying cause of certain age‐related phenotypes. Consistent with this, some hallmarks of immune aging were more prevalent in individuals exposed to whole‐body irradiation (WBI), which leaves no anatomical repository of undamaged hematopoietic cells. To decisively test whether and to what extent WBI in youth will leave a mark on the immune system as it ages, we exposed young male C57BL/6 mice to sublethal WBI (0.5–4 Gy), mimicking human survivor exposure during nuclear catastrophe. We followed lymphocyte homeostasis thorough the lifespan, response to vaccination, and ability to resist lethal viral challenge in the old age. None of the irradiated groups showed significant differences compared with mock‐irradiated (0 Gy) animals for the parameters measured. Even the mice that received the highest dose of sublethal WBI in youth (4 Gy) exhibited equilibrated lymphocyte homeostasis, robust T‐ and B‐cell responses to live attenuated West Nile virus (WNV) vaccine and full survival following vaccination upon lethal WNV challenge. Therefore, a single dose of nonlethal WBI in youth, resulting in widespread DNA damage and repopulation stress in hematopoietic cells, leaves no significant trace of increased immune aging in a lethal vaccine challenge model.