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Regulatory T Cells Modulate DNA Vaccine Immunogenicity at Early Time via Functional CD4(+) T Cells and Antigen Duration.

ABSTRACT: The development of an effective vaccine against HIV has proved to be difficult. Many factors including natural regulatory T cells (Treg cells) can dampen the CD8 T-cell immunogenicity. In this study, we aimed to understand how Treg cells control CD8(+) T-cell immune responses during DNA prime-boost immunization. Animals were immunized with plasmid HIV IIIB gp120 DNA following elimination of Treg cells by administration of anti-CD25 neutralizing antibody. Results demonstrated that the pool size of CD4(+) T cells producing both IL-2 and/or IFN-? (CD4(+)/IL-2(+)/IFN-?(+)) was increased solely during the priming phase. An increment of tetramer binding and intracellular cytokine IFN-? expression, however, were elevated in both primary and secondary stages in CD8(+) T cells. The speed of antigen clearance was also investigated by using DNA luciferase. Surprisingly, DNA luciferase expression was declined to basal level over the ensuing observation period when Treg cells were depleted. Importantly, we found for the first time that DNA expression pattern in Treg-depleted animals was similar to that of the regular memory phase. Moreover, in mice that were exposed to antigen over 5?days prior to Treg cell depletion, CD8(+) T-cell memory response was not affected. Thus, in the present study, we propose a new concept and prove that the enhanced immune response following the depletion of Treg cells during the priming phase likely adds one more set of memory response to the immune system. Taken together, our findings support the notion that Treg cells control DNA vaccine immunogenicity at an early time via antigen duration and functional CD4(+) T-cell responses.

SUBMITTER: Qin L

PROVIDER: S-EPMC4586510 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Regulatory T Cells Modulate DNA Vaccine Immunogenicity at Early Time via Functional CD4(+) T Cells and Antigen Duration.

Qin Lizeng L Jiang Guosheng G Han Jinxiang J Letvin Norman L NL

Frontiers in immunology 20150929

The development of an effective vaccine against HIV has proved to be difficult. Many factors including natural regulatory T cells (Treg cells) can dampen the CD8 T-cell immunogenicity. In this study, we aimed to understand how Treg cells control CD8(+) T-cell immune responses during DNA prime-boost immunization. Animals were immunized with plasmid HIV IIIB gp120 DNA following elimination of Treg cells by administration of anti-CD25 neutralizing antibody. Results demonstrated that the pool size o ...[more]

PMID: 26483796

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Project description:Endothelial cells (ECs) line the luminal surface of blood vessels and have an active role in the recruitment of leukocytes, including immune cell activation. Regulatory T cells (Tregs) are immune suppressor cells that maintain peripheral tolerance and must interact with the endothelium as they traffic into tissue. We hypothesized that human ECs could modulate Tregs and their suppressor function. Cocultures of CD4+ T cells with human umbilical vein ECs (HUVECs) or dermal microvascular ECs (HDMECs) were conducted and analyzed for activation and proliferation after 72 and 120?h using flow cytometry. In monocyte-depleted cultures, human ECs were found to support CD4+ T cell proliferation in the presence of external mitogens phytohemagglutinin or anti-CD3/28 antibodies (aCD3/28). Activation was shown by CD25 expression in these cells that also transiently expressed the Treg transcription factor FOXP3. HUVECs supported the specific concurrent proliferation of both effector T cells and Tregs when cocultured with aCD3/28. Purified Tregs were also functionally activated by prior coculture with EC to suppress effector T (Teff) cell proliferation. Both direct coculture and indirect coculture of EC and Treg showed activation of the Treg suppressive phenotype. However, whereas HUVEC showed enhancement of suppression by both mechanisms, HDMEC only supported Treg suppressive activity via the contact-independent mechanism. In the contact-independent cultures, the soluble mediators IL-6, GM-CSF, or G-CSF released from ECs following interferon-? activation were not responsible for the enhanced Treg suppressor function. Following direct coculture, Treg expression of inhibitory receptors PD-1 and OX40 was elevated while activated EC expressed the counter ligands programmed death ligand (PD-L)1 and PD-L2. Therefore, human ECs have a role in supporting T cell proliferation and increasing Treg suppressor function. This ability of EC to enhance Treg function could offer novel targets to boost Treg activity during inflammatory disorders.

Project description:BackgroundExisting methods to measure influenza vaccine immunogenicity prohibit detailed analysis of epitope determinants recognized by immunoglobulins. The development of highly multiplex proteomics platforms capable of capturing a high level of antibody binding information will enable researchers and clinicians to generate rapid and meaningful readouts of influenza-specific antibody reactivity.MethodsWe developed influenza hemagglutinin (HA) whole-protein and peptide microarrays and validated that the arrays allow detection of specific antibody reactivity across a broad dynamic range using commercially available antibodies targeted to linear and conformational HA epitopes. We derived serum from blood draws taken from 76 young and elderly subjects immediately before and 28±7 days post-vaccination with the 2008/2009 trivalent influenza vaccine and determined the antibody reactivity of these sera to influenza array antigens.ResultsUsing linear regression and correcting for multiple hypothesis testing by the Benjamini and Hochberg method of permutations over 1000 resamplings, we identified antibody reactivity to influenza whole-protein and peptide array features that correlated significantly with age, H1N1, and B-strain post-vaccine titer as assessed through a standard microneutralization assay (p<0.05, q <0.2). Notably, we identified several peptide epitopes that were inversely correlated with regard to age and seasonal H1N1 and B-strain neutralization titer (p<0.05, q <0.2), implicating reactivity to these epitopes in age-related defects in response to H1N1 influenza. We also employed multivariate linear regression with cross-validation to build models based on age and pre-vaccine peptide reactivity that predicted vaccine-induced neutralization of seasonal H1N1 and H3N2 influenza strains with a high level of accuracy (84.7% and 74.0%, respectively).ConclusionOur methods provide powerful tools for rapid and accurate measurement of broad antibody-based immune responses to influenza, and may be useful in measuring response to other vaccines and infectious agents.

Dataset Information

Regulatory T Cells Modulate DNA Vaccine Immunogenicity at Early Time via Functional CD4(+) T Cells and Antigen Duration.

Publications

Regulatory T Cells Modulate DNA Vaccine Immunogenicity at Early Time via Functional CD4(+) T Cells and Antigen Duration.

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