Functional Significance of CD57 Expression on Human NK Cells and Relevance to Disease.

Historically, human NK cells have been identified as CD3(-)CD56(+)CD16(±) lymphocytes. More recently it has been established that CD57 expression defines functionally discrete sub-populations of NK cells. On T cells, CD57 expression has been regarded as a marker of terminal differentiation and (perhaps wrongly) of anergy and senescence. Similarly, CD57 expression seems to identify the final stages of peripheral NK cell maturation; its expression increases with age and is associated with chronic infections, particularly human cytomegalovirus infection. However, CD57(+) NK cells are highly cytotoxic and their presence seems to be beneficial in a number of non-communicable diseases. The purpose of this article is to review our current understanding of CD57 expression as a marker of NK cell function and disease prognosis, as well as to outline areas for further research

Differential activation of CD57-defined natural killer cell subsets during recall responses to vaccine antigens

Natural killer (NK) cells contribute to the effector phase of vaccine-induced adaptive immune responses, secreting cytokines and releasing cytotoxic granules. The proportion of responding NK cells varies between individuals and by vaccine, suggesting that functionally discrete subsets of NK cells with different activation requirements may be involved. Here, we have used responses to individual components of the DTP vaccine [tetanus toxoid (TT), diphtheria toxoid (DT), whole cell inactivated pertussis] to characterize the NK cell subsets involved in interleukin-2-dependent recall responses. Culture with TT, DT or pertussis induced NK cell CD25 expression and interferon-γ production in previously vaccinated individuals. Responses were the most robust against whole cell pertussis, with responses to TT being particularly low. Functional analysis of discrete NK cell subsets revealed that transition from CD56bright to CD56dim correlated with increased responsiveness to CD16 cross-linking, whereas increasing CD57 expression correlated with a loss of responsiveness to cytokines. A higher frequency of CD56dim CD57− NK cells expressed CD25 and interferon-γ following stimulation with vaccine antigen compared with CD56dim CD57+ NK cells and made the largest overall contribution to this response. CD56dim CD57int NK cells represent an intermediate functional phenotype in response to vaccine-induced and receptor-mediated stimuli. These findings have implications for the ability of NK cells to contribute to the effector response after vaccination and for vaccine-induced immunity in older individuals

Synergy between Common γ Chain Family Cytokines and IL-18 Potentiates Innate and Adaptive Pathways of NK Cell Activation

Studies to develop cell-based therapies for cancer and other diseases have consistently shown that purified human natural killer (NK) cells secrete cytokines and kill target cells after in vitro culture with high concentrations of cytokines. However, these assays poorly reflect the conditions that are likely to prevail in vivo in the early stages of an infection and have been carried out in a wide variety of experimental systems, which has led to contradictions within the literature. We have conducted a detailed kinetic and dose-response analysis of human NK cell responses to low concentrations of IL-12, IL-15, IL-18, IL-21, and IFN-α, alone and in combination, and their potential to synergize with IL-2. We find that very low concentrations of both innate and adaptive common γ chain cytokines synergize with equally low concentrations of IL-18 to drive rapid and potent NK cell CD25 and IFN-γ expression; IL-18 and IL-2 reciprocally sustain CD25 and IL-18Rα expression in a positive feedback loop; and IL-18 synergizes with FcγRIII (CD16) signaling to augment antibody-dependent cellular cytotoxicity. These data indicate that NK cells can be rapidly activated by very low doses of innate cytokines and that the common γ chain cytokines have overlapping but distinct functions in combination with IL-18. Importantly, synergy between multiple signaling pathways leading to rapid NK cell activation at very low cytokine concentrations has been overlooked in prior studies focusing on single cytokines or simple combinations. Moreover, although the precise common γ chain cytokines available during primary and secondary infections may differ, their synergy with both IL-18 and antigen-antibody immune complexes underscores their contribution to NK cell activation during innate and adaptive responses. IL-18 signaling potentiates NK cell effector function during innate and adaptive immune responses by synergy with IL-2, IL-15, and IL-21 and immune complexes

Influenza Vaccination Generates Cytokine-Induced Memory-like NK Cells:Impact of Human Cytomegalovirus Infection

Human NK cells are activated by cytokines, immune complexes, and signals transduced via activating ligands on other host cells. After vaccination, or during secondary infection, adaptive immune responses can enhance both cytokine-driven and Ab-dependent NK cell responses. However, induction of NK cells for enhanced function after in vitro exposure to innate inflammatory cytokines has also been reported and may synergize with adaptive signals to potentiate NK cell activity during infection or vaccination. To test this hypothesis, we examined the effect of seasonal influenza vaccination on NK cell function and phenotype in 52 previously unvaccinated individuals. Enhanced, IL-2-dependent, NK cell IFN-γ responses to Influenza A/California/7/2009 virus were detected up to 4 wk postvaccination and higher in human CMV (HCMV)-seronegative (HCMV(-)) individuals than in HCMV-seropositive (HCMV(+)) individuals. By comparison, robust NK cell degranulation responses were observed both before and after vaccination, due to high titers of naturally occurring anti-influenza Abs in human plasma, and did not differ between HCMV(+) and HCMV(-) subjects. In addition to these IL-2-dependent and Ab-dependent responses, NK cell responses to innate cytokines were also enhanced after influenza vaccination; this was associated with proliferation of CD57(-) NK cells and was most evident in HCMV(+) subjects. Similar enhancement of cytokine responsiveness was observed when NK cells were cocultured in vitro with Influenza A/California/7/2009 virus, and this was at least partially dependent upon IFN-αβR2. In summary, our data indicate that attenuated or live viral vaccines promote cytokine-induced memory-like NK cells and that this process is influenced by HCMV infection

Temporal variability and site specificity of thermomechanical weathering in a temperate climate

Thermomechanical processes caused by short- and long-term temperature fluctuations are a prevalent weathering mechanism on exposed rock walls. While many authors have explored the potential for thermomechanical weathering in alpine and polar regions, few have examined the effects of seasonality on weathering in temperate climates. This is pertinent as seasonal climatic conditions may influence both short-term temperature oscillations which produce incipient fractures and diurnal-to annual-scale cycles which propagate pre-existing fractures via thermal fatigue. In this study, three rock outcrops located along the Niagara Escarpment in Hamilton, Canada were monitored to examine changes in the thermal regime at the rock surface and within pre-existing fractures over a 1-year period. Temperature was sampled in 1-min intervals, providing data at a fine temporal resolution. Our unique dataset demonstrates that the rock surface and fracture experience minute-scale temperature oscillations which magnify over time. Longer-term temperature cycles during the year are superimposed upon minute- and diurnal-scale fluctuations which likely augment weathering potential. This produces considerable thermal stress over the year which we estimate to be on the order of 18 GPa at the rock surface and 8 GPa in fractures. We also observed diurnal reversals of the temperature gradient between the rock surface and fracture which may further amplify crack propagation. Seasonality and site-specific characteristics interact to modify different components of the rockwall thermal regime. Vegetation shading has seasonal and diurnal-scale impacts on the temperature gradient between the surface and fracture, and the amplitude of daily warming and cooling cycles. Aspect has a stronger influence on minute-scale temperature oscillations. Estimates of diurnal thermal stress indicate that the thermomechanical weathering potential is seasonally variable, but highest in the spring. Our findings demonstrate that in a temperate climate, rockwall thermal regimes experience variability across the gradient of temporal scale with strong seasonal effects

Malaria Vaccines: Recent Advances and New Horizons.

The development of highly effective and durable vaccines against the human malaria parasites Plasmodium falciparum and P. vivax remains a key priority. Decades of endeavor have taught that achieving this goal will be challenging; however, recent innovation in malaria vaccine research and a diverse pipeline of novel vaccine candidates for clinical assessment provides optimism. With first-generation pre-erythrocytic vaccines aiming for licensure in the coming years, it is important to reflect on how next-generation approaches can improve on their success. Here we review the latest vaccine approaches that seek to prevent malaria infection, disease, and transmission and highlight some of the major underlying immunological and molecular mechanisms of protection. The synthesis of rational antigen selection, immunogen design, and immunization strategies to induce quantitatively and qualitatively improved immune effector mechanisms offers promise for achieving sustained high-level protection

Age-related dynamics of circulating innate lymphoid cells in an African population

Innate lymphoid cell (ILC) lineages mirror those of CD4+ T helper cell subsets, producing type 1, 2 and 3 cytokines respectively. Studies in adult human populations have shown contributions of non-cytotoxic ILC to immune regulation or pathogenesis in a wide range of diseases and have prompted investigations of potential functional redundancy between ILC and T helper cell compartments in neonates and children. To investigate the potential for ILC to contribute to immune responses across the human lifespan, we examined the numbers and frequencies of peripheral blood ILC subsets in a cohort of Gambians aged between 5 and 73 years of age. ILC2 were the most abundant peripheral blood ILC subset in this Gambian cohort, while ILC1 were the rarest at all ages. Moreover, the frequency of ILC1s (as a proportion of all lymphocytes) was remarkably stable over the life course whereas ILC3 cell frequencies and absolute numbers declined steadily across the life course and ILC2 frequencies and absolute numbers declined from childhood until the age of approx. 30 years of age. Age-related reductions in ILC2 cell numbers appeared to be partially offset by increasing numbers of total and GATA3+ central memory (CD45RA-CCR7+) CD4+ T cells, although there was also a gradual decline in numbers of total and GATA3+ effector memory (CD45RA-CCR7-) CD4+ T cells. Despite reduced overall abundance of ILC2 cells, we observed a coincident increase in the proportion of CD117+ ILC2, indicating potential for age-related adaptation of these cells in childhood and early adulthood. While both CD117+ and CD117- ILC2 cells produced IL-13, these responses occurred predominantly within CD117- cells. Furthermore, comparison of ILC frequencies between aged-matched Gambian and UK young adults (25-29 years) revealed an overall higher proportion of ILC1 and ILC2, but not ILC3 in Gambians. Thus, these data indicate ongoing age-related changes in ILC2 cells throughout life, which retain the capacity to differentiate into potent type 2 cytokine producing cells, consistent with an ongoing role in immune modulation

Earth Science Education #7. GeoTrails: Accessible Online Tools for Outreach and Education

As geoscientists, we must prioritize improving our ability to communicate science to the public. Effective geoscience communication enables communities to understand how geological processes have shaped our planet and make informed decisions about Earth’s future. However, geoscience research outputs have traditionally been published in peer-reviewed journals and presented at academic conferences. Consequently, essential information about local geology is rarely available in accessible, open access, and engaging formats. Here, we propose virtual field trips, or ‘GeoTrails’, as a possible solution to address the disconnect between geoscience research and public knowledge by improving our communication to the public. This initiative is largely driven by undergraduate students, who identify points of geological interest along selected hiking trails, write concise descriptions derived from scientific sources (e.g. longer peer-reviewed articles and government reports), and collect field data (e.g. 3-D LiDAR models, drone photography) to illustrate the characteristics of these geological features. The goal of the project is to communicate the importance of local geology on our environment and to raise awareness of how changing climates could affect us in the future; this information can empower communities to make better, more informed planning decisions. The creation of GeoTrails along the Niagara Escarpment offers a promising strategy to highlight the role of geoscientists and to engage the public in our ongoing research that aims to showcase Canada’s geoheritage.En tant que géoscientifiques, nous devons donner la priorité à l’amélioration de notre capacité à communiquer la science au public. Une communication efficace des géosciences permet aux communautés de comprendre comment les processus géologiques ont façonné notre planète et de prendre des décisions éclairées sur l’avenir de la Terre. Cependant, les résultats de la recherche en géosciences ont traditionnellement été publiés dans des revues à comité de lecture et présentés lors de conférences académiques. Par conséquent, les informations essentielles sur la géologie locale sont rarement disponibles sous des formats accessibles, en libre accès et attrayants. Dans cette optique, nous proposons des excursions virtuelles, ou « GeoTrails », comme solution possible pour combler le fossé entre la recherche en géosciences et la connaissance du public en améliorant notre communication avec celui-ci. Cette initiative est en grande partie menée par des étudiants de premier cycle, qui identifient des points d’intérêt géologiques le long de sentiers de randonnée sélectionnés, rédigent des descriptions concises basées sur des sources scientifiques (par exemple, des articles à comité de lecture plus longs et des rapports gouvernementaux) et collectent des données sur le terrain (par exemple, des modèles LiDAR 3-D, des photographies par drone) pour illustrer les caractéristiques de ces caractéristiques géologiques. L'objectif du projet est de communiquer l'importance de la géologie locale sur notre environnement et de sensibiliser aux façons dont les changements climatiques pourraient nous affecter à l'avenir; cette information peut permettre aux communautés de prendre des décisions de planification meilleures et plus éclairées. La création de GeoTrails le long de l'escarpement du Niagara offre une stratégie prometteuse pour mettre en valeur le rôle des géoscientifiques et pour engager le public dans notre recherche en cours qui vise à présenter le patrimoine géologique du Canada

IL-15 Promotes Polyfunctional NK Cell Responses to Influenza by Boosting IL-12 Production

IL-15 is a key regulator of NK cell maintenance and proliferation and synergizes with other myeloid cell-derived cytokines to enhance NK cell effector function. At low concentrations, trans-presentation of IL-15 by dendritic cells can activate NK cells, whereas at higher concentrations it can act directly on NK cells, independently of accessory cells. In this study, we investigate the potential for IL-15 to boost responses to influenza virus by promoting accessory cell function. We find that coculture of human PBMCs with inactivated whole influenza virus (A/Victoria/361/2011) in the presence of very low concentrations of IL-15 results in increased production of myeloid cell-derived cytokines, including IL-12, IFN-α2, GM-CSF, and IL-1β, and an increased frequency of polyfunctional NK cells (defined by the expression of two or more of CD107a, IFN-γ, and CD25). Neutralization experiments demonstrate that IL-15-mediated enhancement of NK cell responses is primarily dependent on IL-12 and partially dependent on IFN-αβR1 signaling. Critically, IL-15 boosted the production of IL-12 in influenza-stimulated blood myeloid dendritic cells. IL-15 costimulation also restored the ability of less-differentiated NK cells from human CMV-seropositive individuals to respond to influenza virus. These data suggest that very low concentrations of IL-15 play an important role in boosting accessory cell function to support NK cell effector functions

Poor CD4+ T Cell Immunogenicity Limits Humoral Immunity to P. falciparum Transmission-Blocking Candidate Pfs25 in Humans.

Plasmodium falciparum transmission-blocking vaccines (TBVs) targeting the Pfs25 antigen have shown promise in mice but the same efficacy has never been achieved in humans. We have previously published pre-clinical data related to a TBV candidate Pfs25-IMX313 encoded in viral vectors which was very promising and hence progressed to human clinical trials. The results from the clinical trial of this vaccine were very modest. Here we unravel why, contrary to mice, this vaccine has failed to induce robust antibody (Ab) titres in humans to elicit transmission-blocking activity. We examined Pfs25-specific B cell and T follicular helper (Tfh) cell responses in mice and humans after vaccination with Pfs25-IMX313 encoded by replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA) delivered in the heterologous prime-boost regimen via intramuscular route. We found that after vaccination, the Pfs25-IMX313 was immunologically suboptimal in humans compared to mice in terms of serum Ab production and antigen-specific B, CD4+ and Tfh cell responses. We identified that the key determinant for the poor anti-Pfs25 Ab formation in humans was the lack of CD4+ T cell recognition of Pfs25-IMX313 derived peptide epitopes. This is supported by correlations established between the ratio of proliferated antigen-specific CD4+/Tfh-like T cells, CXCL13 sera levels, and the corresponding numbers of circulating Pfs25-specific memory B cells, that consequently reflected on antigen-specific IgG sera levels. These correlations can inform the design of next-generation Pfs25-based vaccines for robust and durable blocking of malaria transmission