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Many respiratory viruses, including influenza and SARS-CoV-2, are transmitted via the emission and inhalation of infectious respiratory aerosols in indoor environments. Resuspended particles from indoor surfaces and clothing can be a major source of airborne microbiological contaminants in indoor environments; however, it is unknown whether resuspended viruses contribute substantially to disease transmission. In this study, we investigated the resuspension via human walking activity of influenza A virus H3N2 laboratory strain, which was generated through a nebulizer into a sealed, unventilated biosafety level 2 (BSL-2) laboratory. The mean airborne viral concentrations following the resuspension events (3.7×103 viral RNA copies m−3) were two orders of magnitude lower than those following direct emission via the nebulizer (1.1×105 viral RNA copies m−3). The calculated resuspension emission factor (normalized ratio of the airborne mass to mass available for resuspension on the surface) of 10−3 was similar to reported values for 1–2 μm particles. Thus, depending on the infectious dose and viability of the virus, resuspension of settled respiratory viruses could lead to transmission, but the risk appears to be much lower than for direct respiratory emissions. To our knowledge, this is the first full-scale experimental study designed to quantify virus resuspension.

The presence of a liquid can prevent moving surfaces from coming into intimate contact. With smooth-surfaced rubber, it is possible to examine by optical interferometry the shape and thickness of liquid films between the surfaces. Furthermore, in water lubrication, if the acidity or alkalinity of the water is altered, laboratory friction measurements reveal the impact on its lubricity. Extensive testing shows that some rubber materials are more sensitive to water pH than others, and air aging has an influence on the results. In some circumstances the level of wet friction can decrease by two orders of magnitude—a surprising result by normal lubrication experience. These water pH results are described in some detail and mechanistic explanations are offered. The overall conclusion is that pH and the state of oxidation of a rubber surface can have a marked effect on its water-lubricated friction.

Low-angle annular dark field (LAADF) scanning transmission electron microscopy (STEM) imaging is presented as a method that is sensitive to the oxidation state of cerium ions in CeO2 nanoparticles. This relationship was validated through electron energy loss spectroscopy (EELS), in situ measurements, as well as multislice image simulations. Static displacements caused by the increased ionic radius of Ce(3+) influence the electron channeling process and increase electron scattering to low angles while reducing scatter to high angles. This process manifests itself by reducing the high-angle annular dark field (HAADF) signal intensity while increasing the LAADF signal intensity in close proximity to Ce(3+) ions. This technique can supplement STEM-EELS and in so doing, relax the experimental challenges associated with acquiring oxidation state information at high spatial resolutions.

Research on rubber wiper blades led to the establishment of the now widely used Johnson, Kendall, Roberts (JKR) equilibrium equation that determines the strength of adhesion between surfaces. The equation was adapted to allow for the viscoelasticity of rubber, leading to explanations of how adhesion can impact on tack; rebound resilience; and rolling, static, and sliding friction. The adhesion of rubber to ice was found to depend on salt concentration in the ice, thus providing insight into winter tire performance. The development of optical techniques has greatly aided studies, particularly for measuring the thickness of thin liquid films sandwiched between rubber surfaces. Measurements on water films squeezed between rubber and glass revealed the action of repulsive surface forces that can reduce adhesion and friction. The efficacy of water lubrication depends upon whether surfactants are present and upon the acidity or alkalinity of the water. Improved understanding of adhesion and friction mechanisms offers design guidance for a range of rubber articles.

CD8 and CD4 T cells are each critically important for immune control of murine gammaherpesvirus 68 (γHV68) infection. In immunocompetent mice, acute γHV68 infection results in lifelong latency, but in the absence of CD4 T cell help, mice succumb to viral recrudescence and disease. However, the requirements for CD4 T cell help in the generation and maintenance of antiviral CD8 T cell responses are incompletely understood, and it is unclear whether there are epitope-specific differences in the requirement of CD8 T cells for CD4 help. In this report, we characterized the CD8 T cell response to γHV68 in major histocompatibility complex (MHC) class II −/− mice, which lack CD4 T cells, or after antibody-mediated depletion of CD4 T cells. All antiviral CD8 T cells exhibited marked upregulation of surface expression of the inhibitory receptor programmed death-1 (PD-1), but surprisingly, while the immunodominant memory response appeared to be functionally impaired, helpless CD8 T cells of a subdominant specificity had increased numbers and enhanced functionality. Thus, we demonstrate differential requirements for CD4 help in the antiviral CD8 T cell response to a latent gammaherpesvirus. IMPORTANCE γHV68 is a mouse pathogen closely related to the oncogenic human γHVs, which infect a majority of the world's population. Reactivation of these viruses from latency can lead to complications, disease, and even death. CD4 T cells are required for complete immune control of long-term infection, in part by providing key signals to dendritic cells that in turn instruct optimal antiviral CD8 T cell responses. We have investigated multiple virus-specific CD8 T cell responses during infection and identified a subdominant CD8 T cell response that is numerically and functionally enhanced in the absence of CD4 T cell help. This occurs in spite of high surface expression of an inhibitory receptor and in contrast to the immunodominant response, which is impaired. Our data suggest that signals from CD4 T cells are important in maintaining the CD8 T cell hierarchy during γHV infections.

Human herpesviruses establish lifelong latency. Viral recrudescence can lead to the development of cancers, immunoproliferative disorders, transplantation complications, and thrombocytopenia. Although platelet-specific autoantibodies have been reported in patients infected with the Epstein–Barr virus (EBV), the mechanisms by which thrombocytopenia is induced remain unclear, as do the relative contributions of lytic viral replication and latent viral gene expression. The human gammaherpesviruses are tightly restricted in their ability to infect other mammals, so they are difficult to study in live animal models. Here we show that infection of mice with murine gammaherpesvirus-68 (γHV68), a rodent-specific pathogen closely related to EBV, induces the production of platelet-binding antibodies and causes thrombocytopenia. Infection of antibody-deficient mice does not lead to thrombocytopenia, indicating the platelet decrease is mediated by antibody. Additionally, infection with a latency-null recombinant γHV68 does not induce thrombocytopenia, suggesting factors associated with viral latency drive the infection-induced antibody-mediated thrombocytopenia. These studies describe an important animal model of gammaherpesvirus-induced autoimmune thrombocytopenia and demonstrate that this pathology is mediated by antibody and dependent on viral latency. This model will allow studies of the underlying mechanisms of disease progression and the testing of therapeutic strategies for the alleviation of virus-induced thrombocytopenia.

Regulatory CD4+Foxp3+ T cells (Tregs) are key regulators of inflammatory responses and control the magnitude of cellular immune responses to viral infections. However, little is known about how Tregs contribute to immune regulation during memory responses to previously encountered pathogens. In this study, we used MHC class II tetramers specific for the 311–325 peptide from influenza nucleoprotein (NP311–325/IAb) to track the Ag-specific Treg response to primary and secondary influenza virus infections. During secondary infections, Ag-specific memory Tregs showed accelerated accumulation in the lung-draining lymph node and lung parenchyma relative to a primary infection. Memory Tregs effectively controlled the in vitro proliferation of memory CD8+ cells in an Ag-specific fashion that was MHC class II dependent. When memory Tregs were depleted before secondary infection, the magnitude of the Ag-specific memory CD8+ T cell response was increased, as was pulmonary inflammation and airway cytokine/chemokine expression. Replacement of memory Tregs with naive Tregs failed to restore the regulation of the memory CD8 T cell response during secondary infection. Together, these data demonstrate the existence of a previously undescribed population of Ag-specific memory Tregs that shape the cellular immune response to secondary influenza virus challenges and offer an additional parameter to consider when determining the efficacy of vaccinations.

Orienteers have been physiologically assessed in the past using treadmill protocols designed for road and track runners, neglecting the specific conditions in which they compete. The purpose of the present study was to quantify the agreement between physiological data obtained from a specific field-based protocol with that obtained with a matched laboratory-based assessment. Ten elite orienteers completed a six-stage incremental test in both field and laboratory settings. The field test comprised a marked 803-m course over flat forest terrain, with the participants paced by a bicycle parallel to the course. The laboratory test was conducted on a treadmill at a 4.5% grade. Oxygen consumption and heart rate were measured continuously and blood lactate concentration at the completion of each stage. Regression statistics and an analysis of variance were used to analyse the data. Heart rate, blood lactate concentration, and increased significantly with increases in running speed, but there were no sig...

Two studies explored the relation between ethnicity, attitudes toward body weight, dating behavior, and female body satisfaction. Study 1 found that White men expressed a lighter female ideal weight, more resentment about their girlfriend's weight, and more pressure for their partner's thinness than did Black men. Study 2 found that regardless of their own ethnicity, women who dated White men had lower body mass index (BMI), lower ideal weights, and reported experiencing lower levels of body acceptance by their dating partners. This lack of acceptance was associated with lower levels of body satisfaction. These results support the view that the differing aesthetic preferences of Black and White men contribute to differing levels of body satisfaction among Black and White women.

SummaryInnate recognition of invading pathogens in peripheral tissues results in the recruitment of circulating memory CD8+ T cells to sites of localized inflammation during the early phase of a recall response. However, the mechanisms that control the rapid recruitment of these cells to peripheral sites are poorly understood, particularly in relation to influenza and parainfluenza infections of the respiratory tract. In this study, we demonstrate a crucial role for C-C chemokine receptor 5 (CCR5) in the accelerated recruitment of memory CD8+ T cells to the lung airways during virus challenge. Most importantly, CCR5 deficiency resulted in decreased recruitment of memory T cells expressing key effector molecules and impaired control of virus replication during the initial stages of a secondary response. These data highlight the critical importance of early memory T cell recruitment for the efficacy of cellular immunity in the lung.

Increasing age is associated with the development of CD8+ T cell clonal expansions (TCE) that can dominate the peripheral T cell repertoire and interfere with immune responses to infection and vaccination. Some TCE are driven by chronic infections, consistent with dysregulated outgrowth of T cell clones in response to persistent antigenic stimulation. However, a second class of TCE develops with age in the absence of chronic infections and is poorly understood in terms of origin or Ag dependence. In this study, we present evidence that Ag-specific TCE develop at high frequencies from conventional memory CD8+ T cell pools elicited by nonpersistent influenza and parainfluenza virus infections. Putative TCE occurred in both the central- and effector-memory CD8+ T cell populations and did not require Ag for their maintenance. In addition, they were similar to normal memory T cells in terms of phenotype and function, suggesting that they develop stochastically from the memory T cell pool. These data suggest that memory T cell pools become progressively dysregulated over time and this may have a significant impact on immune responsiveness in the aged.

The capacity of the immune system to mediate effective immune responses to pathogens declines with age. In the case of immune responses to newly encountered antigens, several studies have demonstrated that this decline reflects both a loss of naïve T cells and changes in the repertoire and function of these cells over time. However, comparatively little is known about the impact of age on established memory T cells pools. Here we discuss age-related changes in memory CD8(+) T cell pools elicited by influenza and parainfluenza viruses and the impact of these changes on immunity in general.

The contributions of different subsets of memory CD8+ T cells to recall responses at mucosal sites of infection are poorly understood. Here, we analyzed the CD8+ T cell recall responses to respiratory virus infection in mice and demonstrate that activation markers, such as CD27 and CD43, define three distinct subpopulations of memory CD8+ T cells that differ in their capacities to mount recall responses. These subpopulations are distinct from effector– and central–memory subsets, coordinately express other markers associated with activation status, including CXCR3, CD127, and killer cell lectin-like receptor G1, and are superior to CD62L in predicting the capacity of memory T cells to mediate recall responses. Furthermore, the capacity of vaccines to elicit these memory T cell subpopulations predicted the efficacy of the recall response. These findings extend our understanding of how recall responses are generated and suggest that activation and migration markers define distinct, and unrelated, characteristics of memory T cells.

The purpose of this study was to characterize changes and variability in test performance of swimmers within and between seasons over their elite competitive career. Forty elite swimmers (24 male, 16 female) performed a 7×200-m incremental swimming step test several times each 6-month season (10±5 tests, spanning 0.5–6.0 y). Mixed linear modeling provided estimates of percent change in the mean and individual responses (within-athlete variation as a coefficient of variation) for measures based on submaximal performance (fixed 4-mM lactate), maximal performance (the seventh step) and lean mass (from skinfolds and body mass). Submaximal and maximal swim speed increased within each season from pre to taper phase by ∼2.2% for females and ∼1.5% for males (95% confidence limits ±1.0%), with variable contributions from stroke rate and stroke length. Most of the gains in speed were lost in the off-season, leaving a net average annual improvement of ∼1.0% for females and ∼0.6% for males (±1.0%). For subma...

Although the absolute number of memory CD8+ T cells established in the spleen following antigen encounter remains stable for many years, the relative capacity of these cells to mediate recall responses is not known. Here we used a dual adoptive transfer approach to demonstrate a progressive increase in the quality of memory T cell pools in terms of their ability to proliferate and accumulate at effector sites in response to secondary pathogen challenge. This temporal increase in efficacy occurred in CD62Llo (effector memory) and CD62Lhi (central memory) subpopulations, but was most prominent in the CD62Lhi subpopulation. These data indicate that the contribution of effector memory and central memory T cells to the recall response changes substantially over time.

The specificity of CD8+ T cell responses can vary dramatically between primary and secondary infections. For example, NP366–374/Db- and PA224–233/Db-specific CD8+ T cells respond in approximately equal numbers to a primary influenza virus infection in C57BL/6 mice, whereas NP366–374/Db-specific CD8+ T cells dominate the secondary response. To investigate the mechanisms underlying this changing pattern of immunodominance, we analyzed the role of antigen presentation in regulating the specificity of the T cell response. The data show that both dendritic and nondendritic cells are able to present the NP366–374/Db epitope, whereas only dendritic cells effectively present the PA224–233/Db epitope after influenza virus infection, both in vitro and in vivo. This difference in epitope expression favored the activation and expansion of NP366–374/Db-specific CD8+ memory T cells during secondary infection. The data also show that the immune response to influenza virus infection may involve T cells specific for epitopes, such as PA224–233/Db, that are poorly expressed at the site of infection. In this regard, vaccination with the PA224–233 peptide actually had a detrimental effect on the clearance of a subsequent influenza virus infection. Thus, differential antigen presentation impacts both the specificity of the T cell response and the efficacy of peptide-based vaccination strategies.

CD4 T cells are critical for resistance to Mycobacterium tuberculosis infection, but how effective T cell responses are maintained during chronic infection is not well understood. To address this question we examined the CD4 T cell response to a peptide from ESAT-6 during tuberculosis infection in the mouse. The ESAT-61–20/IAb-specific CD4 T cell response in the lungs, mediastinal lymph nodes, and spleen reached maxima 3–4 wk postinfection, when the bacteria came under the control of the immune response. Once chronic infection was established, the relative frequencies of Ag-specific CD4 T cells were maintained at nearly constant levels for at least 160 days. ESAT-61–20/IAb-specific CD4 T cells that responded in vitro expressed activation markers characteristic of chronically activated effector cells and used a limited Vβ repertoire that was clonally stable in vivo for at least 12 wk. 5-Bromo-2-deoxyuridine incorporation studies indicated a relatively high rate of cell division among both total CD4 and ESAT-61–20/IAb-specific CD4 T cells during acute infection, but the degree of 5-bromo-2-deoxyuridine incorporation by both the CD4 T cells and the Ag-specific cells declined at least 3-fold during chronic infection. The data indicate that the peripheral ESAT-61–20/IAb-specific CD4 T cell response to M. tuberculosis is characterized during the acute phase of infection by a period of extensive proliferation, but once bacterial control is achieved, this is followed during chronic infection by an extended containment phase that is associated with a persistent response of activated, yet more slowly proliferating, T cells.

Nineteen well-trained cyclists (14 males and 5 females, mean initial .VO(2max) 62.3 ml kg(-1 )min(-1)) completed a multistage cycle ergometer test to determine maximal mean power output in 4 min (MMPO(4min)), maximal oxygen uptake (.VO(2max)) and maximal accumulated oxygen deficit (MAOD). The athletes were divided into three groups, each of which completed 5, 10 or 15 days of both a control condition (C) and live high:train low altitude exposure (LHTL). The C groups lived and trained at the ambient altitude of 610 m. The LHTL groups spent 8-10 h night(-1) in normobaric hypoxia at a simulated altitude of 2,650 m, and trained at the ambient altitude of 610 m. The changes to MMPO(4min), .VO(2max) and MAOD in response to LHTL altitude exposure were not significantly different for the 5-, 10- and 15-day treatment periods. For the pooled data from all three treatment periods, there were significant increases in MMPO(4min) [mean (SD) 5.15 (0.83) W kg(-1) vs 5.34 (0.78) W kg(-1)] and MAOD [50.1 (14.2) ml kg(-1) vs 54.9 (13.1) ml kg(-1)] in the LHTL athletes between pre- and post-altitude exposure. There were no significant changes in MMPO(4min) [5.09 (0.76) W kg(-1) vs 5.16 (0.86) W kg(-1)] or MAOD [50.5 (14.1) ml kg(-1) vs 49.1 (13.0) ml kg(-1)] in the C athletes over the corresponding period. There were significant increases in .VO(2max) in the athletes during both the LHTL [63.2 (9.0) ml kg(-1 )min(-1) vs 64.1 (9.0) ml kg(-1 )min(-1)] and C [62.0 (8.6) ml kg(-1 )min(-1) vs 63.4 (9.2) ml kg(-1 )min(-1)] conditions. In these athletes, there was no difference in the impact of 5, 10 or 15 days of LHTL on the increases observed in MMPO(4min), .VO(2max) or MAOD; and LHTL increased MMPO(4min) and MAOD more than training at low altitude alone.

Recent studies have shown that virus-specific effector memory T cells can be recovered from the lung airways long after clearance of a respiratory virus infection. These cells are thought to play an important role in the recall response to secondary viral infection. It is currently unclear whether these cells actually persist at this site or are maintained by continual proliferation and recruitment. In this study, we have analyzed the mechanisms underlying the persistence of memory CD8+ T cells in the lung airway lumina following recovery from a respiratory virus infection. The data identify two distinct populations of memory cells. First, a large population Ag-specific CD8+ T cells is deposited in the airways during the acute response to the virus. These cells persist in a functional state for several weeks with minimal further division. Second, a smaller population of Ag-specific CD8+ T cells is maintained in the lung airways by homeostatic proliferation and migration to lung airways after viral clearance. This rate of proliferation is identical to that observed in the spleen, suggesting that these cells may be recent immigrants from the lymphoid organs. These data have significant implications for vaccines designed to promote cellular immunity at mucosal sites such as the lung.

Studies of identical and non identical twins, especially when there have been differences in the intensity and duration of sports training and competition experience between the twins. have contributed substantially to knowledge of the effects of training on sports perfonnance. Holmer and Astrand (1972) studied one pair of identical twins. only one of whom had extensive training and com'petitive experience in Swimming. When tested for maximal oxygen uptake [V02max) while running there was little difference between the twins (3.61 v 3.56 Lomin-1j (swim trained v non swim trained twin respectively). However as the mode oftesting became more speCific to swimming. differences between the twins became more pronounced [3.36 v 2.71 Lomin-1 for front crawl and 2.74 v 1.84 L°min- 1 for arm only Swimming). Significant genetic effects have been identified in perfonnance characteristics related to maximal enpurance effqrts. including maximal heart rate [HRmax). maximal ventilation (VE",ax) and V02max [Bouchard et al. 1986. Fagard et al. 1991); and in indicators of anaerobic perfonnance capacity. including blood lactate accumulation ([La)) and muscle enzyme responses to intense interval training (Rodas et al. 1998, Simoneau et al. 1986). Howeyer, physiological responses to submaximal exercise such as oxygen uptake [V02). or economy, are less related to heritability [Fagard et al. 1991) and more to training status(Rodas et al. 1998).

The oncogenic γ-herpesviruses EBV and Kaposi sarcoma–associated herpesvirus are ubiquitous human pathogens that establish lifelong latent infections maintained by intermittent viral reactivation and reinfection. Effector CD4 T cells are critical for control of viral latency and in immune therapies for virus-associated tumors. In this study, we exploited γHV68 infection of mice to enhance our understanding of the CD4 T cell response during γ-herpesvirus infection. Using a consensus prediction approach, we identified 16 new CD4 epitope-specific responses that arise during lytic infection. An additional epitope encoded by the M2 protein induced uniquely latency-associated CD4 T cells, which were not detected at the peak of lytic infection but only during latency and were not induced postinfection with a latency-deficient virus. M2-specific CD4 T cells were selectively cytotoxic, produced multiple antiviral cytokines, and sustained IL-2 production. Identification of latency-associated cytolytic CD4 T cells will aid in dissecting mechanisms of CD4 immune control of γ-herpesvirus latency and the development of therapeutic approaches to control viral reactivation and pathology.

The poor correlation between cellular immunity to respiratory virus infections and the numbers of memory CD8+ T cells in the secondary lymphoid organs suggests that there may be additional reservoirs of T cell memory to this class of infection. Here we identify a substantial population of Ag-specific T cells in the lung that persist for several months after recovery from an influenza or Sendai virus infection. These cells are present in high numbers in both the airways and lung parenchyma and can be distinguished from memory cell populations in the spleen and peripheral lymph nodes in terms of the relative frequencies among CD8+ T cells, activation status, and kinetics of persistence. In addition, these cells are functional in terms of their ability to proliferate, express cytolytic activity, and secrete cytokines, although they do not express constitutive cytolytic activity. Adoptive transfer experiments demonstrated that the long-term establishment of activated T cells in the lung did not require infection in the lung by a pathogen carrying the inducing Ag. The kinetics of persistence of Ag-specific CD8+ T cells in the lung suggests that they play a key role in protective cellular immunity to respiratory virus infections.

In this study, the hsp60 and hsp70 heat shock protein antigens ofMycobacterium tuberculosiswere tested as potential vaccine candidates, using purified recombinant protein antigens or antigens encoded in the form of a DNA plasmid vaccine. Guinea pigs vaccinated with a mixture of the two proteins showed no evidence of resistance to low-dose aerosol challenge infection and quickly developed severe lung damage characterized by necrotizing bronchointerstitial pneumonia and bronchiolitis. As a result, we turned instead to a DNA vaccination approach using a plasmid encoding the hsp60 antigen ofM. tuberculosis. Although immunogenic in mice, vaccination with plasmid DNA encoding hsp60 was not protective in that model or in the guinea pig model and again gave rise to similar severe lung damage. This study seriously questions the safety of vaccines against tuberculosis that target highly conserved heat shock proteins.

We have used expression screening of a genomic Mycobacterium tuberculosis library with tuberculosis (TB) patient sera to identify novel genes that may be used diagnostically or in the development of a TB vaccine. Using this strategy, we have cloned a novel gene, termed mtb39a , that encodes a 39-kDa protein. Molecular characterization revealed that mtb39a is a member of a family of three highly related genes that are conserved among strains of M. tuberculosis and Mycobacterium bovis BCG but not in other mycobacterial species tested. Immunoblot analysis demonstrated the presence of Mtb39A in M. tuberculosis lysate but not in culture filtrate proteins (CFP), indicating that it is not a secreted antigen. This conclusion is strengthened by the observation that a human T-cell clone specific for purified recombinant Mtb39A protein recognized autologous dendritic cells infected with TB or pulsed with purified protein derivative (PPD) but did not respond to M. tuberculosis CFP. Purified recombinant Mtb39A elicited strong T-cell proliferative and gamma interferon responses in peripheral blood mononuclear cells from 9 of 12 PPD-positive individuals tested, and overlapping peptides were used to identify a minimum of 10 distinct T-cell epitopes. Additionally, mice immunized with mtb39a DNA have shown increased protection from M. tuberculosis challenge, as indicated by a reduction of bacterial load. The human T-cell responses and initial animal studies provide support for further evaluation of this antigen as a possible component of a subunit vaccine for M. tuberculosis .

The interaction between CD95 and its ligand is an important homeostatic mechanism that leads to the induction of apoptosis in activated T cells. In view of recent evidence that this pathway might be defective in aged mice, this study investigated CD95 expression on T cells in old mice activated by infection with Mycobacterium tuberculosis . The results of the study do not support the hypothesis that CD95 is poorly expressed on CD4 T cells from old mice; instead, it was found that similar numbers of T cells from young and old mice expressed CD95, with the intensity of expression if anything higher on the cells from the old mice. In addition, the study demonstrated that changes in CD44 and CD45RB expression previously observed in young infected mice proceeded in a similar fashion in old animals and, as would be predicted, that CD95 hi expression was primarily associated with CD4 T cells expressing the activated CD44 hi CD45RB hi phenotype.

The results of this study present data in support of the hypothesis that T lymphocytes in both young and old mice infected with virulent Mycobacterium tuberculosis undergo changes in expression of cell surface integrin/adhesion molecules as determined by flow cytometric analysis. These data thus further support the hypothesis that a reduced ability of T-cells in old mice to adequately and promptly accumulate at sites of inflammation induced by bacterial implantation is a central parameter underlying the increased susceptibility of these mice to this intracellular bacterial infection. In addition, however, no changes were observed in terms of the T-cell receptor expression (repertoire) of these animals, indicating that this facet of immunity is preserved in aging.

Virus-specific memory CD8+ T cells persist long after infection is resolved and are important for mediating recall responses to secondary infection. Although the number of memory T cells remains relatively constant over time, little is known about the overall stability of the memory T cell pool, particularly with respect to T cell clonal diversity. In this study we developed a novel assay to measure the composition of the memory T cell pool in large cohorts of mice over time following respiratory virus infection.We find that the clonal composition of the virus-specific memory CD8+ T cell pool begins to change within months of the initial infection. These early clonal perturbations eventually result in large clonal expansions that have been associated with ageing.Maintenance of clonal diversity is important for effective long-term memory responses and dysregulation of the memory response begins early after infection.

Emerging problems with the treatment of infections caused by Mycobacterium avium and Mycobacterium tuberculosis require the development of new models, both in vitro and in vivo, in which new chemotherapeutic and immunotherapeutic approaches can be tested. In this brief review, the use of cell culture models, in which drugs can be tested for their capacity to inhibit mycobacterial growth within the infected host macrophage, and new models in vivo in which drugs and/or cytokines can be tested in infected mice are discussed. In this latter case, new emerging mouse models include animals with engineered gene disruptions, in which severely disseminated infections can be produced, thus mimicking events in severely immunocompromised human patients.

CD8+ T cells lacking CXCR3 and CCR5 expression have impaired contraction and generate an increased number of memory cells after virus infection., The development of T cell memory from naive precursors is influenced by molecular cues received during T cell activation and differentiation. In this study, we describe a novel role for the chemokine receptors CCR5 and CXCR3 in regulating effector CD8+ T cell contraction and memory generation after influenza virus infection. We find that Ccr5−/− Cxcr3−/− cells show markedly decreased contraction after viral clearance, leading to the establishment of massive numbers of memory CD8+ T cells. Ccr5−/− Cxcr3−/− cells show reduced expression of CD69 in the lung during the peak of infection, which coincides with differential localization and the rapid appearance of memory precursor cells. Analysis of single chemokine receptor–deficient cells revealed that CXCR3 is primarily responsible for this phenotype, although there is also a role for CCR5 in the enhancement of T cell memory. The phenotype could be reversed by adding exogenous antigen, resulting in the activation and contraction of Ccr5−/− Cxcr3−/− cells. Similar results were observed during chronic Mycobacterium tuberculosis infection. Together, the data support a model of memory CD8+ T cell generation in which the chemokine-directed localization of T cells within infected tissues regulates antigen encounter and controls the extent of CD8+ T cell activation and differentiation, which ultimately regulates effector versus memory cell fate decisions.

Mice infected with virulent Mycobacterium tuberculosis exhibit an age-related increase in susceptibility to disease. The basis of this susceptibility has previously been shown to reflect an inability of the aged host to generate protective CD4 T cells during the early course of the infection. The results of the present study, however, indicate that the emergence of interferon-γ secreting protective CD4 T cells in such mice is not absent, but merely delayed. Furthermore, flow cytometric analysis of such cells accumulating in the spleens of intravenously infected 24-month-old animals revealed that a large percentage of CD4 cells initially had poor or negative expression of the cell surface markers L-selectin and CD11a, molecules that may be important in the movement of T cells across inflamed endothelial blood vessel surfaces. During the course of the tuberculosis infection the numbers of CD4 cells in the spleens of old mice expressing high levels of these molecules rose to levels similar to those observed in young mice, but by that time the numbers of bacilli in target organs had reached close to fatal levels. These data suggest that the capacity of CD4 cells to cross inflamed endothelial surfaces and home into sites of mycobacterial infection may be deficient in old mice, and hence support the hypothesis that the ensuing delay in accumulating such cells within infected lesions contributes to the increased susceptibility of these animals to disease.

Immune responsiveness declines with age in part due to the development of CD8+ T cell clonal expansions (TCEs) that can dominate the peripheral T cell pool. Although some TCEs arise due to persistent Ag stimulation from chronic infections, others arise in the apparent absence of chronic infection. We have recently shown that this latter class of TCEs can arise over time from the memory CD8+ T cell pool established by an acute viral infection. Unlike TCEs driven by chronic infections, these age-related TCEs do not display the phenotypic and in vitro functional characteristics of exhausted cells. However, the rate at which these age-related TCEs develop from the memory CD8+ T cell pool, as well as their ability to mount a recall response to secondary pathogen challenge in vivo, is not known. In this study, we analyzed large cohorts of mice over time for the development of TCE following Sendai virus infection and found a progressive increase in the appearance of TCEs, such that most mice showed evidence of TCE within the memory T cell pool by 2 y postinfection. Using a dual adoptive transfer approach to address the recall potential of virus-specific TCEs, we also demonstrate that most TCEs examined are poorly responsive to a secondary infection. Therefore, we provide evidence that the development of TCE is a common occurrence due to the progressive dysregulation of the virus-specific memory T cell pool with age, but many TCEs are profoundly defective in their ability to mediate recall responses.

After respiratory virus infections, memory CD8+ T cells are maintained in the lung airways by a process of continual recruitment. Previous studies have suggested that this process is controlled, at least in the initial weeks after virus clearance, by residual antigen in the lung-draining mediastinal lymph nodes (MLNs). We used mouse models of influenza and parainfluenza virus infection to show that intranasally (i.n.) primed memory CD8+ T cells possess a unique ability to be reactivated by residual antigen in the MLN compared with intraperitoneally (i.p.) primed CD8+ T cells, resulting in the preferential recruitment of i.n.-primed memory CD8+ T cells to the lung airways. Furthermore, we demonstrate that the inability of i.p.-primed memory CD8+ T cells to access residual antigen can be corrected by a subsequent i.n. virus infection. Thus, two independent factors, initial CD8+ T cell priming in the MLN and prolonged presentation of residual antigen in the MLN, are required to maintain large numbers of antigen-specific memory CD8+ T cells in the lung airways.

Objective The purpose of this study was to examine how the Five-Factor personality traits moderated the effects of exposure to idealized images on body dissatisfaction in women. Method Sixty-four college women completed the NEO-PI and the Eating Disorder Inventory and were then randomly exposed to images of either thin fashion models or heavier, (“plus-sized”) models. Following presentation of the stimuli, participants completed a second body esteem measure, which was the dependent variable. Results Women high in neuroticism showed significantly greater shifts in body esteem following exposure to media images than did less neurotic women, feeling more dissatisfied with their bodies after viewing idealized images and more satisfied with their bodies after viewing heavier women. Each of the other traits was associated with more favorable self-appraisals following exposure to the idealizing images. Conclusions Of the Five-Factor traits, the harmful effects of idealized images seem to be limited to women with relatively higher levels of neuroticism. These results suggest that the harmful effects of media images may not be as pervasive as is widely believed.

The results of this study show that lipoarabinomannans (LAM) isolated from a virulent strain and from an avirulent strain of Mycobacterium tuberculosis, which have recently been shown to differ markedly in terms of the structures of their nonreducing termini, also differ markedly in the capacity to induce the secretion of tumor necrosis factor from murine macrophages. It was found that LAM from the avirulent H37Ra strain was 100-fold more potent at inducing tumor necrosis factor secretion than LAM from the virulent Erdman strain, thus leading us to hypothesize that the structure of LAM from a given mycobacterial isolate may directly influence its ability to elicit, or avoid, cytokine-mediated mechanisms of host resistance.

Effector T cells are a crucial component of the adaptive immune response to respiratory virus infections. Although it was previously reported that the chemokine receptors CCR5 and CXCR3 affect trafficking of respiratory virus-specific CD8+ T cells, it is unclear whether these receptors govern effector CD4+ T cell migration to the lungs. To assess the role of CCR5 and CXCR3 in vivo, we directly compared the migration of Ag-specific wild-type and chemokine receptor-deficient effector T cells in mixed bone marrow chimeric mice during a parainfluenza virus infection. CXCR3-deficient effector CD4+ T cells were 5- to 10-fold less efficient at migrating to the lung compared with wild-type cells, whereas CCR5-deficient effector T cells were not impaired in their migration to the lung. In contrast to its role in trafficking, CXCR3 had no impact on effector CD4+ T cell proliferation, phenotype, or function in any of the tissues examined. These findings demonstrate that CXCR3 controls virus-specific effector CD4+ T cell migration in vivo, and suggest that blocking CXCR3-mediated recruitment may limit T cell-induced immunopathology during respiratory virus infections.

Increasing age is associated with a decline in adaptive immunity and poorer responses to vaccination. While specific immune defects have clearly been defined in the naive T-cell pool of aged individuals, much less is known about the memory T-cell pool. Current data suggest that T-cell memory generated in an aged individual has a reduced capacity to mediate recall responses due primarily to defects in the proliferative capacity of individual cells. These defective recall responses in the aged can be further compounded by the development of ‘holes’ in the T-cell repertoire due to a dwindling supply of naive T-cell precursors. In contrast, T-cell memory generated in young individuals undergoes a variety of changes over time including both an increase in the proliferative capacity of individual memory T-cells and a decrease in the overall efficacy of the recall response in the lung. Furthermore, the development of T-cell clonal expansions with age can have a dramatic impact on the makeup of the memory T-cell pool, thereby influencing the number of pathogenspecific T-cells capable of participating in the recall response. Collectively, these changes appear to reflect the redistribution of memory T-cell subsets within the memory T-cell pool and the dysregulation of memory T-cell homeostasis over time. This review outlines each of these processes and discusses their implications for vaccination in the elderly.

CD4+T cell responses to aerosolMycobacterium tuberculosis(Mtb) infection are characterized by the relatively delayed appearance of effector T cells in the lungs. This delay in the adaptive response is likely critical in allowing the bacteria to establish persistent infection. Because of limitations associated with the detection of low frequencies of naïve T cells, it had not been possible to precisely determine when and where naïve antigen-specific T cells are first activated. We have addressed this problem by using early secreted antigenic target 6 (ESAT-6)-specific transgenic CD4 T cells to monitor early T cell activationin vivo. By using an adoptive transfer approach, we directly show that T cell priming to ESAT-6 occurs only after 10 days of infection, is initially restricted to the mediastinal lymph nodes, and does not involve other lymph nodes or the lungs. Primed CD4 T cells rapidly differentiated into proliferating effector cells and ultimately acquired the ability to produce IFN-γ and TNF-αex vivo. Initiation of T cell priming was enhanced by two full days depending on the magnitude of the challenge inoculum, which suggests that antigen availability is a factor limiting the early CD4 T cell response. These data define a key period in the adaptive immune response to Mtb infection.

Disseminated Mycobacterium avium infection is the major cause of bacteremia in patients with acquired immunodeficiency syndrome. We present here a new animal model of this disease, thymectomized C57BL/6 mice that were intravenously infused with monoclonal antibody to selectively deplete CD4+ T cells. The increased susceptibility of such animals to M. avium infection is comparable to that of C57BL/6 beige mice and thus may provide a viable alternative to the latter model. Further, using representative strains of acquired immunodeficiency syndrome-associated M. avium (serotypes 1, 4, and 8 and a rough isolate), we show that the course of such infections in thymectomized, CD4-deficient mice can be markedly restrained and in some cases the infections can be sterilized by treatment over a 120-day period with a regimen containing 40 mg of the new antimycobacterial agent rifabutin per kg (body weight).

We show in this study several novel features of T cell-based heterosubtypic immunity against the influenza A virus in mice. First, T cell-mediated heterosubtypic protection against lethal challenge can be generated by a very low priming dose. Second, it becomes effective within 5–6 days. Third, it provides protection against a very high dose challenge for >70 days. Also novel is the finding that strong, long-lasting, heterosubtypic protection can be elicited by priming with attenuated cold-adapted strains. We demonstrate that priming does not prevent infection of the lungs following challenge, but leads to earlier clearance of the virus and 100% survival after otherwise lethal challenge. Protection is dependent on CD8 T cells, and we show that CD4 and CD8 T cells reactive to conserved epitopes of the core proteins of the challenge virus are present after priming. Our results suggest that intranasal vaccination with cold-adapted, attenuated live virus has the potential to provide effective emergency protection against emerging influenza strains for several months.

Proponents of the sociocultural model of eating disorders have suggested that ethnic differences in body dissatisfaction may be diminishing as the thin ideal of beauty becomes more widely disseminated among minority women. In a meta-analysis, the authors examined temporal trends in Black-White differences and also examined whether these differences generalize across various age groups and measures. Results confirmed more favorable body image evaluations among Black than White females, with the greatest differences at the age period of the early 20s. Although results confirmed that ethnic differences have diminished, this trend was limited to weight-focused measures. On more global body image measures, ethnic differences actually increased. These results suggest that the relationship between Black-White ethnicity and body image is more complex than previously suggested.

The response of CD8+ T cells to influenza virus is very sensitive to modulation by aryl hydrocarbon receptor (AhR) agonists; however, the mechanism underlying AhR-mediated alterations in CD8+ T cell function remains unclear. Moreover, very little is known regarding how AhR activation affects anamnestic CD8+ T cell responses. In this study, we analyzed how AhR activation by the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters the in vivo distribution and frequency of CD8+ T cells specific for three different influenza A virus epitopes during and after the resolution of a primary infection. We then determined the effects of TCDD on the expansion of virus-specific memory CD8+ T cells during recall challenge. Adoptive transfer of AhR-null CD8+ T cells into congenic AhR+/+ recipients, and the generation of CD45.2AhR−/−→CD45.1AhR+/+ chimeric mice demonstrate that AhR-regulated events within hemopoietic cells, but not directly within CD8+ T cells, underlie suppressed expansion of virus-specific CD8+ T cells during primary infection. Using a dual-adoptive transfer approach, we directly compared the responsiveness of virus-specific memory CD8+ T cells created in the presence or absence of TCDD, which revealed that despite profound suppression of the primary response to influenza virus, the recall response of virus-specific CD8+ T cells that form in the presence of TCDD is only mildly impaired. Thus, the delayed kinetics of the recall response in TCDD-treated mice reflects the fact that there are fewer memory cells at the time of reinfection rather than an inherent defect in the responsive capacity of virus-specific memory CD8+ cells.

The respiratory tract is characterized by its large surface area and the close association of an extensive vasculature with the external environment. As such, the respiratory tract is a major portal of entry for many pathogens. The immune system is able to effectively control most pulmonary pathogens and establish immunological memory that is capable of mediating an accelerated and enhanced recall response to secondary pathogen challenge. A key component of the recall response in the lung involves the rapid response of antigen-specific memory CD8+ T cells. Recent studies have shown that memory CD8+ T cells are extremely heterogeneous in terms of phenotype, function, anatomical distribution, and longevity. However, we have little understanding of how the different subsets of memory cells actually contribute to the recall response, especially with respect to peripheral or mucosal sites, such as the lung. Since immunological memory is the cornerstone of vaccination, it is essential that we understand how different memory CD8+ T-cell subsets are initially generated, maintained over time, and contribute to recall responses. This review focuses on memory T cells that mediate recall responses to influenza and parainfluenza virus infections in the lung.

International audience; ADP-ribosyl cyclases are structurally conserved enzymes that are best known for catalyzing the production of the calcium-mobilizing metabolite, cyclic adenosine diphosphate ribose (cADPR), from nicotinamide adenine dinucleotide (NAD(+)). However, these enzymes also produce adenosine diphosphate ribose (ADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP(+)), both of which have been shown to modulate calcium mobilization in vitro. We have now characterized a new member of the cyclase family from Schistosoma mansoni, a member of the Platyhelminthes phylum. We show that the novel NAD(P)(+) catabolizing enzyme (NACE) expressed by schistosomes is structurally most closely related to the cyclases cloned from Aplysia but also shows significant homology with the mammalian cyclases, CD38 and CD157. NACE expression is developmentally regulated in schistosomes, and the GPI-anchored protein is localized to the outer tegument of the adult schistosome. Importantly, NACE, like all members of the cyclase family, is a multifunctional enzyme and catalyzes NAD(+) glycohydrolase and base-exchange reactions to produce ADPR and NAADP(+). However, despite being competent to generate a cyclic product from NGD(+), a nonphysiologic surrogate substrate, NACE is so far the only enzyme in the cyclase family that is unable to produce significant amounts of cADPR (

The relative contributions of CD62Lhigh (central) memory and CD62Llow (effector) memory T cell populations to recall responses are poorly understood, especially in the respiratory tract. In this study, we took advantage of a dual-adoptive transfer system in the mouse to simultaneously follow the recall response of effector and central memory subpopulations to intranasal parainfluenza virus infection. Using MHC class I and class II multimers, we tracked the responses of Ag-specific CD8+ and CD4+ memory T cells in the same animals. The data show that effector memory T cells mounted recall responses that were equal to, or greater than, those mounted by central memory T cells. Moreover, effector memory T cells were more efficient at subsequently establishing a second generation of memory T cells. These data contrast with other studies indicating that central memory CD8+ T cells are the prominent contributors to systemic virus infections.

Athletes commonly attempt to enhance performance by training in normoxia but sleeping in hypoxia [live high and train low (LHTL)]. However, chronic hypoxia reduces muscle Na+-K+-ATPase content, whereas fatiguing contractions reduce Na+-K+-ATPase activity, which each may impair performance. We examined whether LHTL and intense exercise would decrease muscle Na+-K+-ATPase activity and whether these effects would be additive and sufficient to impair performance or plasma K+regulation. Thirteen subjects were randomly assigned to two fitness-matched groups, LHTL ( n = 6) or control (Con, n = 7). LHTL slept at simulated moderate altitude (3,000 m, inspired O2fraction = 15.48%) for 23 nights and lived and trained by day under normoxic conditions in Canberra (altitude ∼600 m). Con lived, trained, and slept in normoxia. A standardized incremental exercise test was conducted before and after LHTL. A vastus lateralis muscle biopsy was taken at rest and after exercise, before and after LHTL or Con, and analyzed for maximal Na+-K+-ATPase activity [K+-stimulated 3- O-methylfluorescein phosphatase (3- O-MFPase)] and Na+-K+-ATPase content ([3H]ouabain binding sites). 3- O-MFPase activity was decreased by −2.9 ± 2.6% in LHTL ( P < 0.05) and was depressed immediately after exercise ( P < 0.05) similarly in Con and LHTL (−13.0 ± 3.2 and −11.8 ± 1.5%, respectively). Plasma K+concentration during exercise was unchanged by LHTL; [3H]ouabain binding was unchanged with LHTL or exercise. Peak oxygen consumption was reduced in LHTL ( P < 0.05) but not in Con, whereas exercise work was unchanged in either group. Thus LHTL had a minor effect on, and incremental exercise reduced, Na+-K+-ATPase activity. However, the small LHTL-induced depression of 3- O-MFPase activity was insufficient to adversely affect either K+regulation or total work performed.