T-Cell Memory Responses Elicited by Yellow Fever Vaccine are Targeted to Overlapping Epitopes Containing Multiple HLA-I and -II Binding Motifs

The yellow fever vaccines (YF-17D-204 and 17DD) are considered to be among the safest vaccines and the presence of neutralizing antibodies is correlated with protection, although other immune effector mechanisms are known to be involved. T-cell responses are known to play an important role modulating antibody production and the killing of infected cells. However, little is known about the repertoire of T-cell responses elicited by the YF-17DD vaccine in humans. In this report, a library of 653 partially overlapping 15-mer peptides covering the envelope (Env) and nonstructural (NS) proteins 1 to 5 of the vaccine was utilized to perform a comprehensive analysis of the virus-specific CD4+ and CD8+ T-cell responses. The T-cell responses were screened ex-vivo by IFN-γ ELISPOT assays using blood samples from 220 YF-17DD vaccinees collected two months to four years after immunization. Each peptide was tested in 75 to 208 separate individuals of the cohort. The screening identified sixteen immunodominant antigens that elicited activation of circulating memory T-cells in 10% to 33% of the individuals. Biochemical in-vitro binding assays and immunogenetic and immunogenicity studies indicated that each of the sixteen immunogenic 15-mer peptides contained two or more partially overlapping epitopes that could bind with high affinity to molecules of different HLAs. The prevalence of the immunogenicity of a peptide in the cohort was correlated with the diversity of HLA-II alleles that they could bind. These findings suggest that overlapping of HLA binding motifs within a peptide enhances its T-cell immunogenicity and the prevalence of the response in the population. In summary, the results suggests that in addition to factors of the innate immunity, "promiscuous" T-cell antigens might contribute to the high efficacy of the yellow fever vaccines. © 2013 de Melo et al

A Temporal Role Of Type I Interferon Signaling in CD8+ T Cell Maturation during Acute West Nile Virus Infection

A genetic absence of the common IFN- α/β signaling receptor (IFNAR) in mice is associated with enhanced viral replication and altered adaptive immune responses. However, analysis of IFNAR-/- mice is limited for studying the functions of type I IFN at discrete stages of viral infection. To define the temporal functions of type I IFN signaling in the context of infection by West Nile virus (WNV), we treated mice with MAR1-5A3, a neutralizing, non cell-depleting anti-IFNAR antibody. Inhibition of type I IFN signaling at or before day 2 after infection was associated with markedly enhanced viral burden, whereas treatment at day 4 had substantially less effect on WNV dissemination. While antibody treatment prior to infection resulted in massive expansion of virus-specific CD8+ T cells, blockade of type I IFN signaling starting at day 4 induced dysfunctional CD8+ T cells with depressed cytokine responses and expression of phenotypic markers suggesting exhaustion. Thus, only the later maturation phase of anti-WNV CD8+ T cell development requires type I IFN signaling. WNV infection experiments in BATF3-/- mice, which lack CD8-α dendritic cells and have impaired priming due to inefficient antigen cross-presentation, revealed a similar effect of blocking IFN signaling on CD8+ T cell maturation. Collectively, our results suggest that cell non-autonomous type I IFN signaling shapes maturation of antiviral CD8+ T cell response at a stage distinct from the initial priming event

Measuring, and identifying predictors of, women's perceptions of three types of breast cancer risk: population risk, absolute risk and comparative risk

Although a key function of cancer genetics services is to provide risk information, to date there has been little consistency in the way in which breast cancer risk perception has been measured. The aims of the study were to measure estimates of (i) population risk, (ii) absolute risk and (iii) comparative risk of developing breast cancer for Ashkenazi Jewish women, and to determine predictors of breast cancer risk perception. Of 152 women, 107 (70%) completed all questions. The mean (s.d.) estimates for population risk, absolute risk and comparative risk were 22.7% (15.9), 31.8% (20.6) and 1.9-fold (1.9), respectively. Most women overestimated population risk. Women at population risk generally overestimated the population risk and their own absolute risk, yet understood they are at the same risk as the population. Those with a family history understood that they are at increased risk, but underestimated the extent to which their familial risk is increased. Anxiety, high estimation of population risk and lesser family history predicted overestimation of absolute risk, whereas high estimation of population risk and a strong family history predicted underestimation of comparative risk

Angular and Current-Target Correlations in Deep Inelastic Scattering at HERA

Correlations between charged particles in deep inelastic ep scattering have been studied in the Breit frame with the ZEUS detector at HERA using an integrated luminosity of 6.4 pb-1. Short-range correlations are analysed in terms of the angular separation between current-region particles within a cone centred around the virtual photon axis. Long-range correlations between the current and target regions have also been measured. The data support predictions for the scaling behaviour of the angular correlations at high Q2 and for anti-correlations between the current and target regions over a large range in Q2 and in the Bjorken scaling variable x. Analytic QCD calculations and Monte Carlo models correctly describe the trends of the data at high Q2, but show quantitative discrepancies. The data show differences between the correlations in deep inelastic scattering and e+e- annihilation.Comment: 26 pages including 10 figures (submitted to Eur. J. Phys. C

The tetanic depression in fast motor units of mammalian skeletal muscle can be evoked by lengthening of one initial interpulse interval

A lower than expected tetanic force (the tetanic depression) is regularly observed in fast motor units (MUs) when a higher stimulation frequency immediately follows a lower one. The aim of the present study was to determine whether prolongation of only the first interpulse interval (IPI) resulted in tetanic depression. The experiments were carried out on fast MUs of the medial gastrocnemius muscle in cats and rats. The tetanic depression was measured in each case as the force decrease of a tetanus with one IPI prolonged in relation to the tetanic force at the respective constant stimulation frequency. Force depression was observed in all cases studied and was considerably greater in cats. For cats, the mean values of force depression amounted to 28.64% for FR and 10.86% for FF MUs whereas for rats 9.30 and 7.21% for FR and FF motor units, respectively. Since the phenomenon of tetanic depression in mammalian muscle is commonly observed even after a change in only the initial interpulse interval within a stimulation pattern, it can effectively influence processes of force regulation during voluntary activity of a muscle, when motoneurones progressively increase the firing rate

Protective Efficacy of Serially Up-Ranked Subdominant CD8+ T Cell Epitopes against Virus Challenges

Immunodominance in T cell responses to complex antigens like viruses is still incompletely understood. Some data indicate that the dominant responses to viruses are not necessarily the most protective, while other data imply that dominant responses are the most important. The issue is of considerable importance to the rational design of vaccines, particularly against variable escaping viruses like human immunodeficiency virus type 1 and hepatitis C virus. Here, we showed that sequential inactivation of dominant epitopes up-ranks the remaining subdominant determinants. Importantly, we demonstrated that subdominant epitopes can induce robust responses and protect against whole viruses if they are allowed at least once in the vaccination regimen to locally or temporally dominate T cell induction. Therefore, refocusing T cell immune responses away from highly variable determinants recognized during natural virus infection towards subdominant, but conserved regions is possible and merits evaluation in humans

Behavioural and demographic predictors of adherence to three consecutive faecal occult blood test screening opportunities: a population study

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background Social cognitive variables are often examined for their association with initial participation in colorectal cancer screening. Few studies have examined the association of these variables with adherence to multiple screening offers i.e., rescreening. This study aimed to describe patterns of participatory behaviour after three rounds of screening using faecal immunochemical tests (FIT) and to determine social cognitive, demographic and background variables predictive of variations in adherence. Methods Participants were 1,540 men and women aged 50 to 75 living in South Australia who completed a behavioural survey measuring demographic (for example, age, gender) and social cognitive variables relevant to FIT screening (for example, perceived barriers, benefits, self-efficacy). The survey was followed by three, free FIT screening offers mailed on an annual basis from 2008 to 2010. Patterns of participation after three screening rounds were described as one of five screening behaviours; 1) consistent re-participation (adherent with all screening rounds), 2) consistent refusal (adherent with no screening rounds), 3) drop out (adherent with earlier but not later rounds), 4) intermittent re-participation (adherent with alternate rounds) and 5) delayed entry (adherent with later but not initial round(s)). Univariate (Chi Square and Analysis of Variance) and multivariate (Generalised Estimating Equations) analyses were conducted to determine variables predictive of each category of non-adherence (those that did not participate in every screening offer, groups 2, 3, 4 and 5) relative to consistent re-participation. Results Significant social cognitive predictors of non-adherence were; less self-efficacy (drop out and consistent refusal), greater perceived barriers (drop out) and lower levels of response efficacy (consistent refusal). Demographic predictors of non-adherence included; male gender (delayed entry), younger age (intermittent, delayed and consistent refusal), less frequent GP visits (intermittent re-participation) and lack of adequate health insurance (drop out). Less satisfaction with screening at baseline predicted drop out, consistent refusal and delayed entry. Conclusions Different combinations of demographic and behavioural variables predicted different patterns of rescreening adherence. Rescreening interventions may benefit from a targeted approach that considers the different needs of the population subgroups. Satisfaction with past FOBT screening measured prior to the study screening offers was an important predictor of adherence

Buffered memory: a hypothesis for the maintenance of functional, virus-specific CD8(+) T cells during cytomegalovirus infection.

Chronic infections have been a major topic of investigation in recent years, but the mechanisms that dictate whether or not a pathogen is successfully controlled are incompletely understood. Cytomegalovirus (CMV) is a herpesvirus that establishes a persistent infection in the majority of people in the world. Like other herpesviruses, CMV is well controlled by an effective immune response and induces little, if any, pathology in healthy individuals. However, controlling CMV requires continuous immune surveillance, and thus, CMV is a significant cause of morbidity and death in immune-compromised individuals. T cells in particular play an important role in controlling CMV and both CD4(+) and CD8(+) CMV-specific T cells are essential. These virus-specific T cells persist in exceptionally large numbers during the infection, traffic into peripheral tissues and remain functional, making CMV an attractive vaccine vector for driving CMV-like T cell responses against recombinant antigens of choice. However, the mechanisms by which these T cells persist and differentiate while remaining functional are still poorly understood, and we have no means to promote their development in immune-compromised patients at risk for CMV disease. In this review, I will briefly summarize our current knowledge of CMV-specific CD8(+) T cells and propose a mechanism that may explain their maintenance and preservation of function during chronic infection

Influenza-Specific T Cells from Older People Are Enriched in the Late Effector Subset and Their Presence Inversely Correlates with Vaccine Response

T cells specific for persistent pathogens accumulate with age and express markers of immune senescence. In contrast, much less is known about the state of T cell memory for acutely infecting pathogens. Here we examined T cell responses to influenza in human peripheral blood mononuclear cells from older (>64) and younger (<40) donors using whole virus restimulation with influenza A (A/PR8/34) ex vivo. Although most donors had pre-existing influenza reactive T cells as measured by IFNγ production, older donors had smaller populations of influenza-responsive T cells than young controls and had lost a significant proportion of their CD45RA-negative functional memory population. Despite this apparent dysfunction in a proportion of the older T cells, both old and young donors' T cells from 2008 could respond to A/California/07/2009 ex vivo. For HLA-A2+ donors, MHC tetramer staining showed that a higher proportion of influenza-specific memory CD8 T cells from the 65+ group co-express the markers killer cell lectin-like receptor G1 (KLRG1) and CD57 compared to their younger counterparts. These markers have previously been associated with a late differentiation state or immune senescence. Thus, memory CD8 T cells to an acutely infecting pathogen show signs of advanced differentiation and functional deterioration with age. There was a significant negative correlation between the frequency of KLRG1+CD57+ influenza M1-specific CD8 T cells pre-vaccination and the ability to make antibodies in response to vaccination with seasonal trivalent inactivated vaccine, whereas no such trend was observed when the total CD8+KLRG1+CD57+ population was analyzed. These results suggest that the state of the influenza-specific memory CD8 T cells may be a predictive indicator of a vaccine responsive healthy immune system in old age

Regulation of immunity during visceral Leishmania infection

Unicellular eukaryotes of the genus Leishmania are collectively responsible for a heterogeneous group of diseases known as leishmaniasis. The visceral form of leishmaniasis, caused by L. donovani or L. infantum, is a devastating condition, claiming 20,000 to 40,000 lives annually, with particular incidence in some of the poorest regions of the world. Immunity to Leishmania depends on the development of protective type I immune responses capable of activating infected phagocytes to kill intracellular amastigotes. However, despite the induction of protective responses, disease progresses due to a multitude of factors that impede an optimal response. These include the action of suppressive cytokines, exhaustion of specific T cells, loss of lymphoid tissue architecture and a defective humoral response. We will review how these responses are orchestrated during the course of infection, including both early and chronic stages, focusing on the spleen and the liver, which are the main target organs of visceral Leishmania in the host. A comprehensive understanding of the immune events that occur during visceral Leishmania infection is crucial for the implementation of immunotherapeutic approaches that complement the current anti-Leishmania chemotherapy and the development of effective vaccines to prevent disease.The research leading to these results has received funding from the European Community’s Seventh Framework Programme under grant agreement No.602773 (Project KINDRED). VR is supported by a post-doctoral fellowship granted by the KINDReD consortium. RS thanks the Foundation for Science and Technology (FCT) for an Investigator Grant (IF/00021/2014). This work was supported by grants to JE from ANR (LEISH-APO, France), Partenariat Hubert Curien (PHC) (program Volubilis, MA/11/262). JE acknowledges the support of the Canada Research Chair Program