NF-κB-regulated suppression of T-bet in T cells represses Th1 immune responses in pregnancy

ABSTRACT Chronic infection with Friend retrovirus is associated with suppressed antitumor immune responses. In the present study we investigated whether modulation of T-cell responses during acute infection would restore antitumor immunity in persistently infected mice. T-cell modulation was done by treatments with DTA-1 anti- glucocorticoid-induced tumor necrosis factor receptor monoclonal antibodies. The DTA-1 monoclonal antibody is nondepleting and delivers costimulatory signals that both enhance the activation of effector T cells and inhibit suppression by regulatory T cells. DTA-1 therapy produced faster Th1 immune responses, significant reductions in both acute virus loads and pathology and, most importantly, long-term improvement of CD8+ T-cell-mediated antitumor responses.

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CD4+ T cells and IL-4-mediated support of Th1 immune responses

Trends in Immunology ◽

10.1016/s1471-4906(02)02220-2 ◽

2002 ◽

Vol 23 (6) ◽

pp. 280

Author(s):

Mark P Rubinstein ◽

David J Cole

Keyword(s):

T Cells ◽

Immune Responses ◽

Cd4 T Cells ◽

Th1 Immune Responses

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Decidual immune response following COVID-19 during pregnancy varies by timing of maternal SARS-CoV-2 infection

10.1101/2021.11.20.469369 ◽

2021 ◽

Author(s):

Lillian J Juttukonda ◽

Elisha M Wachman ◽

Jeffery Boateng ◽

Mayuri Jain ◽

Yoel Benarroch ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Immune Responses ◽

Nk Cells ◽

Control Group ◽

Decidua Basalis ◽

Tnf Α ◽

Show Evidence ◽

Negative Controls ◽

In Pregnancy

While COVID-19 infection during pregnancy is common, fetal transmission is rare, suggesting that intrauterine mechanisms form an effective blockade against SARS-CoV-2. Key among these is the decidual immune environment of the placenta. We hypothesized that decidual leukocytes are altered by maternal SARS-CoV-2 infection in pregnancy and that this decidual immune resonse is shaped by the timing of infection during gestation. To address this hypothesis, we collected decidua basalis tissues at delivery from women with symptomatic COVID-19 during second (2nd Tri COVID, n=8) or third trimester (3rd Tri COVID, n=8) and SARS-CoV-2-negative controls (Control, n=8). Decidual natural killer (NK) cells, macrophages and T cells were evaluated using quantitative microscopy, and pro- and anti-inflammatory cytokine mRNA expression was evaluated using quantitative reverse transcriptase PCR (qRT-PCR). When compared with the Control group, decidual tissues from 3rd Tri COVID exhibited significantly increased macrophages, NK cells and T cells, whereas 2nd Tri COVID only had significantly increased T cells. In evaluating decidual cytokine expression, we noted that IL-6, IL-8, IL-10 and TNF-α were significantly correlated with macrophage cell abundance. However, in 2nd Tri COVID tissues, there was significant downregulation of IL-6, IL-8, IL-10, and TNF-α. Taken together, these results suggest innate and adaptive immune responses are present at the maternal-fetal interface in maternal SARS-CoV-2 infections late in pregnancy, and that infections earlier in pregnancy show evidence of a resolving immune response. Further studies are warranted to characterize the full scope of intrauterine immune responses in pregnancies affected by maternal COVID-19.

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Propionibacterium acnes vaccination induces regulatory T cells and Th1 immune responses and improves mouse atopic dermatitis

Experimental Dermatology ◽

10.1111/j.1600-0625.2010.01180.x ◽

2011 ◽

Vol 20 (2) ◽

pp. 157-158 ◽

Cited By ~ 17

Author(s):

Hiroshi Kitagawa ◽

Keiichi Yamanaka ◽

Masato Kakeda ◽

Hiroyasu Inada ◽

Yasutomo Imai ◽

...

Keyword(s):

T Cells ◽

Atopic Dermatitis ◽

Regulatory T Cells ◽

Immune Responses ◽

Propionibacterium Acnes ◽

Th1 Immune Responses

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GII.P16-GII.2 Recombinant Norovirus VLPs Polarize Macrophages Into the M1 Phenotype for Th1 Immune Responses

Frontiers in Immunology ◽

10.3389/fimmu.2021.781718 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ji Cheng Han ◽

Qiu Xuan Li ◽

Jin Bo Fang ◽

Jin Yong Zhang ◽

Yi Quan Li ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Antigen Presentation ◽

Cd4 T Cells ◽

Vaccine Development ◽

Expression System ◽

Baculovirus Expression System ◽

Humoral Immune ◽

Underlying Mechanisms ◽

Th1 Immune Responses

Norovirus (NoV) is a zoonotic virus that causes diarrhea in humans and animals. Outbreaks in nosocomial settings occur annually worldwide, endangering public health and causing serious social and economic burdens. The latter quarter of 2016 witnessed the emergence of the GII.P16-GII.2 recombinant norovirus throughout Asia. This genotype exhibits strong infectivity and replication characteristics, proposing its potential to initiate a pandemic. There is no vaccine against GII.P16-GII.2 recombinant norovirus, so it is necessary to design a preventive vaccine. In this study, GII.P16-GII.2 type norovirus virus-like particles (VLPs) were constructed using the baculovirus expression system and used to conduct immunizations in mice. After immunization of mice, mice were induced to produce memory T cells and specific antibodies, indicating that the VLPs induced specific cellular and humoral immune responses. Further experiments were then initiated to understand the underlying mechanisms involved in antigen presentation. Towards this, we established co-cultures between dendritic cells (DCs) or macrophages (Mø) and naïve CD4+T cells and simulated the antigen presentation process by incubation with VLPs. Thereafter, we detected changes in cell surface molecules, cytokines and related proteins. The results indicated that VLPs effectively promoted the phenotypic maturation of Mø but not DCs, as indicated by significant changes in the expression of MHC-II, costimulatory factors and related cytokines in Mø. Moreover, we found VLPs caused Mø to polarize to the M1 type and release inflammatory cytokines, thereby inducing naïve CD4+ T cells to perform Th1 immune responses. Therefore, this study reveals the mechanism of antigen presentation involving GII.P16-GII.2 recombinant norovirus VLPs, providing a theoretical basis for both understanding responses to norovirus infection as well as opportunities for vaccine development.

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286.Nuclear factor κB downregulation in human T-cells is essential for the maintenance of the cytokine profile required for pregnancy success

Reproduction Fertility and Development ◽

10.1071/srb04abs286 ◽

2004 ◽

Vol 16 (9) ◽

pp. 286

Author(s):

S. A. McCracken ◽

E. D.M. Gallery ◽

J. M. Morris

Keyword(s):

T Cells ◽

Immune Responses ◽

Molecular Mechanisms ◽

Protein Transport ◽

Cytokine Profile ◽

Nuclear Factor ◽

Mobility Shift ◽

Pregnant Females ◽

Th 1 ◽

In Pregnancy

Human pregnancy is associated with a shift away from Th-1 type and a bias towards Th-2 type immune responses. The molecular mechanisms that regulate this are unknown. We assessed the expression and activity of Nuclear Factor (NF)-κB, a transcription factor that plays a central role in regulating immune responses. Nuclear and cytoplasmic fractions were prepared from isolated T-cells from non-pregnant and pregnant females and subjected to Western blotting to assess NF-κB and its' inhibitors IκBα and β expression. NF-κB activity in nuclear extracts was determined by Electrophoretic Mobility Shift Assays. Isolated T-cells were pre-incubated with/without the NF-κB translocation inhibitor SN50 and subsequently stimulated with PMA/ionomycin in the presence of the protein transport inhibitor Brefeldin A. Cytokine production was determined using flow cytometry. Our results demonstrated high levels of immunoreactive NF-κB (p65) in all nuclear fractions of T-cells from non-pregnant females. In contrast, low levels of p65 were detected in nuclear fractions of T-cells from pregnant females. Levels of IκBα and β were also higher in cytoplasmic fractions of T-cells from non-pregnant than from pregnant females. The reduction in p65 levels in pregnancy was consistent with reduced levels of active NF-κB in T-cells from pregnant relative to non-pregnant females. Stimulation of T-cells from non-pregnant females with PMA/ionomycin resulted in IκBα degradation, p65 translocation and subsequent production of Th-1 cytokines IFN-β and IL-2. In contrast, PMA stimulation had no effect on NF-κB activity in T-cells from pregnant females and a reduced effect on IFN-β and IL-2 production. In the presence of SN50, IFN-β and IL-2 production by T-cells from non-pregnant females was attenuated demonstrating a specific role for NF-κB in the production of these Th-1 cytokines. We can therefore conclude that, specific down-regulation of NF-κB in T-cells in pregnancy is an essential requirement for maintaining the cytokine profile necessary for pregnancy success.

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Aryloxy Triester Phosphonamidates of Phosphoantigens Exhibit Favorable Stability and Potent Activation of Vγ9/Vδ2 T‐Cells

10.26434/chemrxiv.6755033.v1 ◽

2018 ◽

Cited By ~ 1

Author(s):

Hachemi Kadri ◽

Taher E. Taher ◽

Qin Xu ◽

Richard T. Bryan ◽

Benjamin E. Willcox ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Serum Stability ◽

T Cell Immune Responses ◽

Further Development

We previously reported the application of the aryloxy triester phosphoramidate prodrug technology to the phosphoantigen (E)-4-hydroxybut-2-enyl phosphate (HMBP). Although these prodrugs exhibited potent activation of Vγ9/Vδ2 T‐cell immune responses, their stability was low due to the rapid cleavage of the -O-P- bond. To address this, we herein report the application of the same prodrug strategy to two HMBP phosphonates, which have stable -CH2-P- or -CF2-P- bonds. These HMBP phosphonate prodrugs, phosphonamidates, exhibited excellent serum stability and potent activation of Vgama9/Vdelta2 T‐cells making them attractive compounds for further development as potential immunotherapeutics.

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Aryloxy Triester Phosphonamidates of Phosphoantigens Exhibit Favorable Stability and Potent Activation of Vγ9/Vδ2 T‐Cells

10.26434/chemrxiv.6755033 ◽

2018 ◽

Author(s):

Hachemi Kadri ◽

Taher E. Taher ◽

Qin Xu ◽

Richard T. Bryan ◽

Benjamin E. Willcox ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Serum Stability ◽

T Cell Immune Responses ◽

Further Development

We previously reported the application of the aryloxy triester phosphoramidate prodrug technology to the phosphoantigen (E)-4-hydroxybut-2-enyl phosphate (HMBP). Although these prodrugs exhibited potent activation of Vγ9/Vδ2 T‐cell immune responses, their stability was low due to the rapid cleavage of the -O-P- bond. To address this, we herein report the application of the same prodrug strategy to two HMBP phosphonates, which have stable -CH2-P- or -CF2-P- bonds. These HMBP phosphonate prodrugs, phosphonamidates, exhibited excellent serum stability and potent activation of Vgama9/Vdelta2 T‐cells making them attractive compounds for further development as potential immunotherapeutics.

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