Gene gun DNA immunization of cattle induces humoral and CD4 T-cell-mediated immune responses against the Theileria parva polymorphic immunodominant molecule

Until recently, immune responses in filovirus survivors remained poorly understood. Early studies revealed IgM and IgG responses to infection with various filoviruses, but recent outbreaks have greatly expanded our understanding of filovirus immune responses. Immune responses in survivors of Ebola virus (EBOV) and Sudan virus (SUDV) infections have provided the most insight, with T cell responses as well as detailed antibody responses having been characterized. Immune responses to Marburg virus (MARV), however, remain almost entirely uncharacterized. We report that immune responses in MARV survivors share characteristics with EBOV and SUDV infections but have some distinct differences. MARV survivors developed multivariate CD4+ T cell responses but limited CD8+ T cell responses, more in keeping with SUDV survivors than EBOV survivors. In stark contrast to SUDV survivors, rare neutralizing antibody responses in MARV survivors diminished rapidly after the outbreak. These results warrant serious consideration for any vaccine or therapeutic that seeks to be broadly protective, as different filoviruses may require different immune responses to achieve immunity.

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Miquelianin Inhibits Allergic Responses in Mice by Suppressing CD4+ T Cell Proliferation

Antioxidants ◽

10.3390/antiox10071120 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1120

Author(s):

Dae Woon Choi ◽

Sun Young Jung ◽

Gun-Dong Kim ◽

So-Young Lee ◽

Hee Soon Shin

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Mouse Model ◽

Immune Responses ◽

Reactive Oxygen Species Generation ◽

Allergic Diseases ◽

Cd4 T Cell ◽

Th2 Cells ◽

T Cell Proliferation ◽

Heme Oxygenase 1

Allergic diseases, including atopic dermatitis (AD), induce type 2 helper T (Th2) cell-dominant immune responses. Miquelianin (quercetin 3-O-glucuronide, MQL) is an active compound in Rosae multiflorae fructus extract with anti-allergic properties. Here, we investigate the anti-allergic effects of MQL in an ovalbumin (OVA)-induced Th2-dominant mouse model and the associated mechanisms. Oral MQL suppressed cytokine and IL-2 production and proliferation of Th2 cells and upregulated heme oxygenase-1 (HO-1) in splenocytes. Ex vivo MQL suppressed Th1- and Th2-related immune responses by inhibiting CD4+ T cell proliferation, and upregulated HO-1 in CD4+ T cells by activating C-Raf–ERK1/2–Nrf2 pathway via induction of reactive oxygen species generation. In a trimellitic anhydride-induced AD-like mouse model, both topical and oral MQL ameliorated AD symptoms by suppressing Th2 immune responses. Our results suggest that MQL is a potential therapeutic agent for CD4+ T cell-mediated diseases, including allergic diseases.

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Plasma Membrane Calcium ATPase Regulates Stoichiometry of CD4+ T-Cell Compartments

Frontiers in Immunology ◽

10.3389/fimmu.2021.687242 ◽

2021 ◽

Vol 12 ◽

Author(s):

Maylin Merino-Wong ◽

Barbara A. Niemeyer ◽

Dalia Alansary

Keyword(s):

Plasma Membrane ◽

T Cell ◽

Immune Responses ◽

Chromatin Immunoprecipitation ◽

Expression Patterns ◽

Calcium Atpase ◽

Cd4 T Cell ◽

Plasma Membrane Calcium Atpase ◽

Cell Compartments

Immune responses involve mobilization of T cells within naïve and memory compartments. Tightly regulated Ca2+ levels are essential for balanced immune outcomes. How Ca2+ contributes to regulating compartment stoichiometry is unknown. Here, we show that plasma membrane Ca2+ ATPase 4 (PMCA4) is differentially expressed in human CD4+ T compartments yielding distinct store operated Ca2+ entry (SOCE) profiles. Modulation of PMCA4 yielded a more prominent increase of SOCE in memory than in naïve CD4+ T cell. Interestingly, downregulation of PMCA4 reduced the effector compartment fraction and led to accumulation of cells in the naïve compartment. In silico analysis and chromatin immunoprecipitation point towards Ying Yang 1 (YY1) as a transcription factor regulating PMCA4 expression. Analyses of PMCA and YY1 expression patterns following activation and of PMCA promoter activity following downregulation of YY1 highlight repressive role of YY1 on PMCA expression. Our findings show that PMCA4 adapts Ca2+ levels to cellular requirements during effector and quiescent phases and thereby represent a potential target to intervene with the outcome of the immune response.

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CT Antigen-Specific Immune Response From DAC/DC Vaccine Correlates With Clinical Outcome In Patients With Relapsed Neuroblastoma

Blood ◽

10.1182/blood.v122.21.2023.2023 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2023-2023

Author(s):

Deepa Kolaseri Krishnadas ◽

Fanqi Bai ◽

Kenneth Lucas

Keyword(s):

Immune Response ◽

T Cell ◽

Immune Responses ◽

Cell Response ◽

T Cell Response ◽

Specific Immune Response ◽

Cd4 T Cell ◽

Dc Vaccine ◽

Ct Antigen ◽

Ct Antigens

Abstract Neuroblastoma is the most common solid tumor in children in the first year of life. Despite high-dose chemotherapy, irradiation and autologous stem cell transplantation, nearly half of these patients relapse, a group for whom there are limited treatment options. The cancer-testis (CT) antigens MAGE-A1, MAGE-A3 and NY-ESO-1 are expressed on neuroblastoma cells in low levels and we have previously shown that the demethylating chemotherapy drug decitabine (DAC) can upregulate the expression of CT antigens in neuroblastoma. We developed a clinical study combining DAC to upregulate CT antigens followed by a dendritic cell (DC) vaccine targeting CT antigens MAGE-A1, MAGE-A3 and NY-ESO-1. Here we report the effects of DAC/DC vaccine in generating antigen-specific immune response and evaluate if there exists a correlation between development of antigen-specific immune responses and clinical responses. The treatment regimen includes 4 cycles of therapy, each consisting of DAC 10mg/m2/day for 5 days, followed by 2 weekly vaccinations consisting of autologous DC pulsed with overlapping peptide mixes derived from full length MAGE-A1, MAGE-A3 and NY-ESO-1. The number of DC administered in the vaccine was based on patient weight, and ranged from 3 to 10 x106 cells. The topical TLR agonist imiquimod was used at the site of vaccination to facilitate immune responses to the vaccine. Peripheral blood was collected weekly to assess antigen-specific immune response. Peripheral blood mononuclear cells were archived at various time points, stimulated for 24 h with MAGE-A1, MAGE-A3 and NY-ESO-1 peptide mixes and studied for the presence of CD137+ antigen-specific cells by flow cytometry. The regimen was well tolerated and highly feasible. We were able to culture DC for 10/10 neuroblastoma patients enrolled on the study. Development of an antibody or a T cell response to the vaccine was defined as either new onset or a two fold increase in the level of antibodies or number of MAGE-A1, MAGE-A3 and NY-ESO-1 specific, CD137+ T cells over baseline levels. The clinical and immunological outcomes of seven neuroblastoma patients treated so far with the DAC/CT antigen vaccine is summarized in table 1. Two patients are in complete remission, one of whom is two years from completing therapy, and another patient is 9 months from therapy. Both these patients demonstrated an increase in the number of circulating CD3+CD8+CD137+ and CD3+CD4+CD137+ T cells against one of the CT antigens in the vaccine. Of the five patients who had disease progression, one had a partial response to his chemotherapy and radiation resistant tumor 2 months post-vaccine. This patient had an antibody response to these antigens post-vaccination but no CD8+ or CD4+ T cell response. Another patient who had no evidence of disease for 8 months following the last vaccine prior to disease recurrence had an antigen-specific CD8+ T cell response against MAGE-A1, MAGE-A3 and NY-ESO-1 antigens but no CD4+ T cell response. These data indicate that DAC/DC vaccine targeting MAGE-A1, MAGE-A3 and NY-ESO-1 are efficient in generating an antigen-specific immune response in four of seven patients studied and there exist a correlation between the presence of immune response and positive clinical outcome. Disclosures: No relevant conflicts of interest to declare.

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DNA Vaccines Encoding Ii-PADRE Generates Potent PADRE-specific CD4+ T-Cell Immune Responses and Enhances Vaccine Potency

Molecular Therapy ◽

10.1038/sj.mt.6300121 ◽

2007 ◽

Vol 15 (6) ◽

pp. 1211-1219 ◽

Cited By ~ 52

Author(s):

Chien-Fu Hung ◽

Ya-Chea Tsai ◽

Liangmei He ◽

T-C Wu

Keyword(s):

T Cell ◽

Immune Responses ◽

Dna Vaccines ◽

Cd4 T Cell ◽

Vaccine Potency ◽

T Cell Immune Responses

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Enhancement of CD4+ T-cell help reverses the doxorubicin-induced suppression of antigen-specific immune responses in vaccinated mice

Gene Therapy ◽

10.1038/gt.2008.79 ◽

2008 ◽

Vol 15 (16) ◽

pp. 1176-1183 ◽

Cited By ~ 7

Author(s):

D Kim ◽

A Monie ◽

Y-C Tsai ◽

L He ◽

M-C Wang ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Cd4 T Cell ◽

Cd4 T Cell Help ◽

T Cell Help

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SIV and Mycobacterium tuberculosis synergy within the granuloma accelerates the reactivation pattern of latent tuberculosis

10.1101/2020.02.21.959353 ◽

2020 ◽

Cited By ~ 2

Author(s):

Collin R Diedrich ◽

Tara Rutledge ◽

Pauline Maiello ◽

Tonilynn M Baranowski ◽

Alexander G White ◽

...

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

Risk Factor ◽

T Cell ◽

Immune Responses ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Bacterial Burden ◽

Common Risk Factor ◽

Immunodeficiency Virus

AbstractHuman immunodeficiency virus infection is the most common risk factor for severe forms of tuberculosis (TB), regardless of CD4 T cell count. Using a well-characterized cynomolgus macaque model of human TB, we compared radiographic, immunologic and microbiologic characteristics of early (subclinical) reactivation of latent M. tuberculosis (Mtb) infection among animals subsequently infected with simian immunodeficiency virus (SIV) or who underwent anti-CD4 depletion by a depletion antibody. CD4 depleted animals had significantly fewer CD4 T cells within granulomas compared to Mtb/SIV co-infected and Mtb-only control animals. After 2 months of treatment, subclinical reactivation occurred at similar rates among CD4 depleted (5 of 7 animals) and SIV infected animals (4 of 8 animals). However, SIV-induced reactivation was associated with more dissemination of lung granulomas that were permissive to Mtb growth resulting in greater bacterial burden within granulomas compared to CD4 depleted reactivators. Granulomas from Mtb/SIV animals displayed a more robust T cell activation profile (IFN-α, IFN-γ, TNF, IL-17, IL-2, IL-10, IL-4 and granzyme B) compared to Mtb/αCD4 animals and controls though these effectors did not protect against reactivation or dissemination, but instead may be related to increased viral and/or Mtb antigens. SIV replication within the granuloma was associated with reactivation, greater overall Mtb growth and Mtb killing resulting in greater overall Mtb burden. These data support that SIV disrupts protective immune responses against latent Mtb infection beyond the loss of CD4 T cells, and that synergy between SIV and Mtb occurs within granulomas.Author SummaryMost humans are able to control infection with Mycobacterium tuberculosis (Mtb), the bacteria that causes tuberculosis (TB). Controlled, asymptomatic infection (latent infection) can develop into symptomatic, severe TB (reactivation TB) when the immune system is impaired, and HIV is the most common risk factor. Chronic HIV infection is associated with low CD4 T cells but there are likely other factors involved. Using macaques with latent Mtb infection, we could induce reactivation from either CD4 T cell depletion or SIV infection. We found that SIV induced reactivation was more dramatic with more bacterial dissemination and bacterial growth compared to those with CD4 depletion. While SIV-infected animals had more activated immune responses in the lung granulomas (a collection of immune cells that functions to combat Mtb), they could not prevent bacterial spread of Mtb resulting in more TB pathology, higher bacterial burden and disease throughout the body. These data suggest that the HIV-induced reactivation TB is not solely from the loss of CD4 T cells. Furthermore, our data suggest that SIV and Mtb have a synergistic relationship within granulomas that impairs the ability to kill Mtb and that this relationship exacerbates TB disease.

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Altered gut microbiota correlate with different immune response to HAART in HIV-infected individuals

10.21203/rs.3.rs-44062/v3 ◽

2020 ◽

Author(s):

Yirui Xie ◽

Jia Sun ◽

Li Wei ◽

Haiyin Jiang ◽

Caiqin Hu ◽

...

Keyword(s):

T Cell ◽

Gut Microbiota ◽

Immune Responses ◽

Immune Activation ◽

Highly Active Antiretroviral Therapy ◽

Cd4 T Cell ◽

Healthy Controls ◽

Cell Counts ◽

Relative Abundances ◽

Gut Microbiota Dysbiosis

Abstract Background: Although gut microbiota dysbiosis has been reported in HIV infected individuals recently, the relationship between the gut microbiota and immune activation in patients with different immune responses to highly active antiretroviral therapy (HAART) is still not well understood. Gut microbiota and immune activation were studied in 36 non-HIV-infected subjects (healthy controls) and 58 HIV-infected individuals, including 28 immunological responders (IR) and 30 immunological non-responders (INR) (≥500 and <200 CD4+ T-cell counts/µl after 2 years of HIV-1 viral suppression respectively) without comorbidities. Results: Metagenome sequencing revealed that HIV-infected immunological responders and immunological non-responders could not recover completely from the gut microbiota dysbiosis. At a 97% similarity level, the relative abundances of Fusobacterium, Ruminococcus gnavus and Megamonas were greater, whereas Faecalibacterium, Alistipes, Bifidobacterium, Eubacterium rectale and Roseburia were more depleted in the IR and INR groups than those in the healthy controls. Ruminococcaceae and Alistipes were positively correlated with nadir and current CD4+ T-cell counts, but negatively correlated with CD8+CD57+ T-cell counts . Inflammation markers and translocation biomarkers (LPS) levels were positively correlated with the abundances of genus Ruminococcus and Fusobacterium but were negatively correlated with the genus Faecalibacterium . The relative abundances of Escherichia-Shigella and Blautia were significantly higher in the IR than those in the INR group. Escherichia-Shigella were negatively correlated with the CD4/CD8 ratio but positively correlated with the amount of C D8+CD57+ T-cells. Roseburia and Blautia were negatively associated with nadir CD4+ T-cell and positively associated with CD8+CD57+ T-cell counts. Conclusions: Gut microbiota dysbiosis may be one of the factors contributing to different immune responses and treatment outcomes to HAART.

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