Systems immunology approaches were employed to investigate innate and adaptive immune responses to influenza and pneumococcal vaccines. These two non-live vaccines show different magnitudes of ...transcriptional responses at different time points after vaccination. Software solutions were developed to explore correlates of vaccine efficacy measured as antibody titers at day 28. These enabled a further dissection of transcriptional responses. Thus, the innate response, measured within hours in the peripheral blood, was dominated by an interferon transcriptional signature after influenza vaccination and by an inflammation signature after pneumococcal vaccination. Day 7 plasmablast responses induced by both vaccines was more pronounced after pneumococcal vaccination. Together, these results suggest that comparing global immune responses elicited by different vaccines will be critical to our understanding of the immune mechanisms underpinning successful vaccination.
► Influenza vaccination elicits a potent interferon signature carried by neutrophils ► Pneumococcal vaccination induces early inflammatory, myeloid transcriptional profile ► Pneumococcal vaccination elicits a potent antibody-secreting cell signature
In the search for a therapeutic HIV-1 vaccine, we describe herein the development of a monocyte-derived dendritic cell (DC) vaccine loaded with a mixture of HIV-1-antigen lipopeptides (ANRS ...HIV-LIPO-5 Vaccine). LIPO-5 is comprised of five HIV-1-antigen peptides (Gag17–35, Gag253–284, Nef66–97, Nef116–145, and Pol325–355), each covalently linked to a palmitoyl-lysylamide moiety. Monocytes enriched from HIV-1-infected highly active antiretroviral therapy (HAART)-treated patients were cultured for three days with granulocyte–macrophage colony-stimulating factor and alpha-interferon. At day 2, the DCs were loaded with ANRS HIV-LIPO-5 vaccine, activated with lipopolysaccharide, harvested at day 3 and frozen. Flow cytometry analysis of thawed DC vaccines showed expression of DC differentiation markers: CD1b/c, CD14, HLA-DR, CD11c, co-stimulatory molecule CD80 and DC maturation marker CD83. DCs were capable of eliciting an HIV-1-antigen-specific response, as measured by expansion of autologous CD4+ and CD8+ T-cells. The expanded T-cells secreted gamma-IFN and interleukin (IL)-13, but not IL-10. The safety and immunogenicity of this DC vaccine are being evaluated in a Phase I/II clinical trial in chronically HIV-1-infected patients on HAART (clinicaltrials.gov identifier: NCT00796770).
Efforts aimed at restoring robust immune responses limiting human immunodeficiency virus (HIV)‐1 replication therapeutically are warranted. We report that vaccination with dendritic cells generated ...ex vivo and loaded with HIV lipopeptides in patients (n = 19) on antiretroviral therapy was well tolerated and immunogenic. Vaccination increased: (i) the breadth of the immune response from 1 (1–3) to 4 (2–5) peptide‐pool responses/patient (p = 0.009); (ii) the frequency of functional T cells (producing at least two cytokines among IFN‐γ, TNF‐α, and IL‐2) from 0.026 to 0.32% (p = 0.002) and from 0.26 to 0.35% (p = 0.005) for CD4+ and CD8+ T cells, respectively; and (iii) the breadth of cytokines secreted by PBMCs upon antigen exposure, including IL‐2, IFN‐γ, IL‐21, IL‐17, and IL‐13. Fifty percent of patients experienced a maximum of viral load (VL) 1 log10 lower than the other half following antiretroviral treatment interruption. An inverse correlation was found between the maximum of VL and the frequency of polyfunctional CD4+ T cells (p = 0.007), production of IL‐2 (p = 0.006), IFN‐γ (p = 0.01), IL‐21 (p = 0.006), and IL‐13 (p = 0.001). These results suggest an association between vaccine responses and a better control of viral replication. These findings will help in the development of strategies for a functional cure for HIV infection.
Nitrogen limitation in Escherichia coli activates about 100 genes. Their expression requires the response regulator NtrC (also called nitrogen regulator I or NRI). Phosphorylation of the ...amino-terminal domain (NTD) of NtrC activates the neighboring central domain and leads to transcriptional activation from promoters that require σ54-containing RNA polymerase. The NTD has five β strands alternating with five α helices. Phosphorylation of aspartate 54 has been shown to reposition α helix 3 to β strand 5 (the “3445 face”) within the NTD. To further study the interactions between the amino-terminal and central domains, we isolated strains with alterations in the NTD that were able to grow on a poor nitrogen source in the absence of phosphorylation by the cognate sensor kinase. We identified strains with alterations located in the 3445 face and α helix 5. Both types of alterations stimulated central domain activities. The α helix 5 alterations differed from those in the 3445 face. They did not cause a large scale conformational change in the NTD, which is not necessary for transcriptional activation in these mutants. Yeast two-hybrid analysis indicated that substitutions in both α helix 5 and the 3445 face diminish the interaction between the NTD and the central domain. Our results suggest that α helix 5 of the NTD, in addition to the 3445 face, interacts with the central domain. We present a model of interdomain signal transduction that proposes different functions for α helix 5 and the 3445 face.
A first look: JRA's author fellowship program Harrod, Carson; Derrick, Deborah B; Cuhel-Schuckers, Amy
The journal of research administration,
03/2016, Letnik:
47, Številka:
1
Journal Article
To encourage research administrators who may not have experience writing journal articles to submit manuscripts for publication, the JRu4 Editorial Board wanted to develop an author fellowship ...program to guide new authors through the process of manuscript preparation. Additionally, there will be several opportunities to learn about the J1L4 Author Fellowship Program at the SRA Annual Conference in San Antonio, Texas (October 22-26, 2016). * Saturday: A Half-Day Preconference Workshop entitled 'Stepping Stones to Becoming a Peer-Reviewed Journal Author' (WS2) * Tuesday: A Concurrent Session entitled 'The Importance and Conduct of Scholarly Writing as Research Administrators' (T102) * Tuesday: A Learning Cafe entitled 'Journal of Research Administration Editorial Chat' (LC6) The J1L4 Editorial Board is excited about this new program to help new authors navigate writing a first publication.
Seasonal influenza vaccine protects 60 to 90% of healthy young adults from influenza infection. The immunological events that lead to the induction of protective antibody responses remain poorly ...understood in humans. We identified the type of CD4+ T cells associated with protective antibody responses after seasonal influenza vaccinations. The administration of trivalent split-virus influenza vaccines induced a temporary increase of CD4+ T cells expressing ICOS, which peaked at day 7, as did plasmablasts. The induction of ICOS was largely restricted to CD4+ T cells coexpressing the chemokine receptors CXCR3 and CXCR5, a subpopulation of circulating memory T follicular helper cells. Up to 60% of these ICOS+CXCR3+CXCR5+CD4+ T cells were specific for influenza antigens and expressed interleukin-2 (IL-2), IL-10, IL-21, and interferon-γ upon antigen stimulation. The increase of ICOS+CXCR3+CXCR5+CD4+ T cells in blood correlated with the increase of preexisting antibody titers, but not with the induction of primary antibody responses. Consistently, purified ICOS+CXCR3+CXCR5+CD4+ T cells efficiently induced memory B cells, but not naïve B cells, to differentiate into plasma cells that produce influenza-specific antibodies ex vivo. Thus, the emergence of blood ICOS+CXCR3+CXCR5+CD4+ T cells correlates with the development of protective antibody responses generated by memory B cells upon seasonal influenza vaccination.
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