scholarly journals Identification and Validation of Nutrient State-Dependent Serum Protein Mediators of Human CD4+ T Cell Responsiveness

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1492
Author(s):  
Kim Han ◽  
Komudi Singh ◽  
Matthew J. Rodman ◽  
Shahin Hassanzadeh ◽  
Yvonne Baumer ◽  
...  
Keyword(s):  
T Cell ◽  
Serum Protein ◽  
Mononuclear Cells ◽  
Serum Proteins ◽  
Biological Effects ◽  
Receptor Activation ◽  
Partial Least Square ◽  
Least Square ◽  
Cd4 T Cell ◽  
Intermittent Fasting

Intermittent fasting and fasting mimetic diets ameliorate inflammation. Similarly, serum extracted from fasted healthy and asthmatic subjects’ blunt inflammation in vitro, implicating serum components in this immunomodulation. To identify the proteins orchestrating these effects, SOMAScan technology was employed to evaluate serum protein levels in healthy subjects following an overnight, 24-h fast and 3 h after refeeding. Partial least square discriminant analysis identified several serum proteins as potential candidates to confer feeding status immunomodulation. The characterization of recombinant IGFBP1 (elevated following 24 h of fasting) and PYY (elevated following refeeding) in primary human CD4+ T cells found that they blunted and induced immune activation, respectively. Furthermore, integrated univariate serum protein analysis compared to RNA-seq analysis from peripheral blood mononuclear cells identified the induction of IL1RL1 and MFGE8 levels in refeeding compared to the 24-h fasting in the same study. Subsequent quantitation of these candidate proteins in lean versus obese individuals identified an inverse regulation of serum levels in the fasted subjects compared to the obese subjects. In parallel, IL1RL1 and MFGE8 supplementation promoted increased CD4+ T responsiveness to T cell receptor activation. Together, these data show that caloric load-linked conditions evoke serological protein changes, which in turn confer biological effects on circulating CD4+ T cell immune responsiveness.

scholarly journals The Role of β-Catenin in Th1 Immune Response against Tuberculosis and Profiles of Expression in Patients with Pulmonary Tuberculosis

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Kunlong Xiong ◽  
Jinxia Niu ◽  
Ruijuan Zheng ◽  
Zhonghua Liu ◽  
Yanzheng Song ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Cd4 T Cell ◽  
Cell Frequency ◽  
Tnf Α ◽  
Ifn Γ

β-Catenin is a key molecule of canonical Wnt/β-catenin pathway. Its roles and expression profiles in T cells of tuberculosis (TB) remain unclear. The aim of this study was to explore the role of β-catenin in CD4+ T cells and its expression characteristics in patients with pulmonary tuberculosis (PTB). In this study, CD4+ T cell-specific β-catenin conditional knockout mice (β-CAT-cKO mice) were aerosol infected with Mycobacteria tuberculosis (Mtb) H37RV with wild-type mice as controls. Four weeks after infection, the mRNA expression of IFN-γ, TNF-α, and TCF-7 in the lungs of mice was measured. CD4, CD8, β-catenin, IFN-γ, and TNF-α in mononuclear cells from the lungs and spleens were measured by flow cytometry, and the pathological changes of lungs were also observed. Patients with PTB were enrolled, with blood samples collected and PBMCs isolated. The expressions of β-catenin, IFN-γ, TNF-α, and PD-1 in CD4+ and CD8+ T cells were measured by flow cytometry. Results showed a decreased frequency of and reduced IFN-γ/TNF-α mRNA expression and secretion by CD4+ T cells in the lungs of infected β-CAT-cKO mice compared with infected wild-type controls, and only slightly more inflammatory changes were observed in the lungs. β-catenin expressions in CD4+ and CD8+ T cells were significantly decreased in blood cells of patients with severe PTB compared with those in mild PTB. The stimulation of peripheral blood mononuclear cells (PBMCs) with lithium chloride (LiCl), a stimulant of β-catenin, resulted in the increase in CD4+ T cell frequency, as well as their secretion of IFN-γ and TNF-α. β-Catenin demonstrated a moderately positive correlation with PD-1 in CD4+ T cells. β-Catenin along with PD-1 and IFN-γ in CD4+ T cells had a high correlation with those in CD8+ T cells. In conclusion, β-catenin may be involved in the regulation of Th1 response and CD4+ T cell frequency in TB.

scholarly journals Identification of Novel HLA Class II-Restricted Neoantigens Derived from Driver Mutations

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 266 ◽  
Author(s):  
Susumu Iiizumi ◽  
Junya Ohtake ◽  
Naoko Murakami ◽  
Taku Kouro ◽  
Mamoru Kawahara ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Immunotherapy ◽  
Mononuclear Cells ◽  
T Cell Responses ◽  
Class Ii ◽  
Hla Class Ii ◽  
Cd4 T Cell ◽  
Driver Mutations ◽  
Cell Responses ◽  
Kit D816v

Neoantigens derived from tumor-specific genetic mutations might be suitable targets for cancer immunotherapy because of their high immunogenicity. In the current study, we evaluated the immunogenicity of 10 driver mutations that are frequently expressed in various cancers using peripheral blood mononuclear cells from healthy donors (n = 25). Of the 10 synthetic peptides (27-mer) derived from these mutations, the six peptides from KRAS-G12D, KRAS-G12R, KRAS-G13D, NRAS-Q61R, PIK3CA-H1047R, and C-Kit-D816V induced T cell responses, suggesting that frequent driver mutations are not always less immunogenic. In particular, immune responses to PIK3CA-H1047R, C-Kit-D816V, KRAS-G13D, and NRAS-Q61R were observed in more than 10% of the donors. All six peptides induced human leukocyte antigen (HLA) class II-restricted CD4+ T cell responses; notably, PIK3CA-H1047R contained at least two different CD4+ T cell epitopes restricted to different HLA class II alleles. In addition, PIK3CA-H1047R and C-Kit-D816V induced antigen-specific CD8+ T cells as well, indicating that they might contain both HLA class I- and class II-restricted epitopes. Since the identified neoantigens might be shared by patients with various types of cancers and are not easily lost due to immune escape, they have the potential to be promising off-the-shelf cancer immunotherapy targets in patients with the corresponding mutations.

Design, creation and in vitro testing of a reduced immunogenicity humanized anti-CD25 monoclonal antibody that retains functional activity

2019 ◽  
Vol 32 (12) ◽  
pp. 543-554
Author(s):  
Marcia Stickler ◽  
Anita Reddy ◽  
Joanna M Xiong ◽  
Melanie H Wong ◽  
Yoshiko Akamatsu ◽  
...  
Keyword(s):  
T Cell ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Cell Epitope ◽  
Cd4 T Cell ◽  
Peripheral Blood Mononuclear ◽  
Epitope Region ◽  
Human Sequence ◽  
Amino Acid Mutations

Abstract Humanized and fully human sequence-derived therapeutic antibodies retain the capacity to induce anti-drug antibodies. Daclizumab (humanized version of the murine anti-Tac antibody; E.HAT) was selected for a proof of concept application of engineering approaches to reduce potential immunogenicity due to its demonstrated immunogenicity in the clinic. Reduced immunogenicity variants of E.HAT were created by identifying and modifying a CD4+ T cell epitope region in the VH region. Variant epitope region peptides were selected for their reduced capacity to induce CD4+ T cell proliferative responses in vitro. Variant antibody molecules were created, and CD25 affinity and potency were similar to the unmodified parent antibody. Fab fragments from the variant antibodies induced a lower frequency and magnitude of responses in human peripheral blood mononuclear cells proliferation tests. By the empirical selection of two amino acid mutations, fully functional humanized E.HAT antibodies with reduced potential to induce immune responses in vitro were created.

scholarly journals Therapeutic Prediction of HIV-1 DNA Decay: A Multicenter Longitudinal Cohort Study

2020 ◽  
Author(s):  
Yongsong Yue ◽  
Yijia Li ◽  
Yizhi Cui ◽  
Nidan Wang ◽  
Yunda Huang ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Count ◽  
Predictive Model ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Cd4 T Cell ◽  
Peripheral Blood Mononuclear ◽  
Treatment Naïve ◽  
Hiv 1 ◽  
Cd4 T Cell Count

Abstract Background: Factors predicting peripheral blood total HIV-1 DNA size in chronically infected patients with successfully suppressed viremia remain unclear. Prognostic power of such factors are of clinical significance for making clinical decisions.Methods: Total HIV-1 DNA in blood at baseline, 12, 24, 48, 96, and 288 weeks after combined antiretroviral therapy (cART) initiation in 607 treatment-naïve patients with chronic HIV-1 infection were quantified. Generalized estimating equations and logistic regression methods were used to derive and validate a predictive model of total HIV-1 DNA after 96 weeks of cART.Results: The total HIV-1 DNA rapidly decreased from baseline [mean = 3.04 log10 copies/106 peripheral blood mononuclear cells (PBMCs)] to week 24 (mean = 2.51 log10 copies/106 PBMCs), and leveled off afterwards. Of the 490 patients who had successful HIV-1 RNA suppression by 96 w post-cART, 92 (18.8%) had a low total HIV-1 DNA count (<100 copies/106 PBMCs) at week 96. In the predictive model, lower baseline total HIV-1 DNA [risk ratio (RR) = 0.08, per 1 log10 copies/106 PBMCs, P < 0.001] and higher baseline CD4+ T cell count (RR = 1.72, per 100 cells/μL, P < 0.001) were significantly associated with a low total HIV-1 DNA count at week 96. In an independent cohort of 117 patients, this model achieved a sensitivity of 75.00% and specificity of 69.52%.Conclusions: The derived model based on baseline total HIV-1 DNA and CD4+ T cell count provides a useful prognostic tool in predicting HIV-1 DNA reservoir control during cART.

scholarly journals T cells instruct dendritic cells to produce inflammasome independent IL-1β causing systemic inflammation

2018 ◽  
Author(s):  
Aakanksha Jain ◽  
Ricardo A. Irizarry-Caro ◽  
Amanpreet S. Chawla ◽  
Naomi H. Philip ◽  
Kaitlin R. Carroll ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Systemic Inflammation ◽  
Cd4 T Cells ◽  
Mechanistic Explanation ◽  
Receptor Activation ◽  
Cd4 T Cell ◽  
Inflammasome Activation ◽  
Autoimmune Pathology

AbstractWhile IL-1β is critical for anti-microbial host defense, it is also a key mediator of autoimmune inflammation. Inflammasome activation following pathogenic insults is known to result in IL-1β production. However, the molecular events that produce IL-1β during T cell driven autoimmune diseases remain unclear. Here, we have discovered an inflammasome-independent pathway of IL-1β production that is triggered upon cognate interactions between dendritic cells and effector CD4 T cells. Analogous to inflammasome activation, this “T cell-instructed IL-1β also relies on two independent signaling events. TNFα produced by activated CD4 T cells engages TNFR signaling on DCs leading to pro-IL-1β synthesis. Subsequently, FasL, also expressed by effector CD4 T cells, engages Fas on DCs leading to caspase-8 dependent pro-IL-1β cleavage. Remarkably, this two-step mechanism is completely independent of pattern recognition receptor activation. IL-1β produced upon cognate DC-effector CD4 T cell interaction causes wide spread leukocyte infiltration, a hallmark of systemic inflammation as well as autoimmune pathology. This study has uncovered a novel feature of DC-T cell cross-talk that allows for active IL-1β secretion independent of innate sensing pathways and provides a mechanistic explanation for IL-1β production and its downstream consequences in CD4 T cell driven autoimmune pathology.

scholarly journals MAVS Genetic Variation Is Associated with Decreased HIV-1 Replication In Vitro and Reduced CD4+ T Cell Infection in HIV-1-Infected Individuals

Viruses ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 764
Author(s):  
Melissa Stunnenberg ◽  
Lisa van Pul ◽  
Joris K. Sprokholt ◽  
Karel A. van Dort ◽  
Sonja I. Gringhuis ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Viral Load ◽  
T Cell ◽  
Viral Replication ◽  
Mononuclear Cells ◽  
Cd4 T Cell ◽  
Lower Percentage ◽  
Cell Counts ◽  
Hiv 1

The mitochondrial antiviral protein MAVS is a key player in the induction of antiviral responses; however, human immunodeficiency virus 1 (HIV-1) is able to suppress these responses. Two linked single nucleotide polymorphisms (SNPs) in the MAVS gene render MAVS insensitive to HIV-1-dependent suppression, and have been shown to be associated with a lower viral load at set point and delayed increase of viral load during disease progression. Here, we studied the underlying mechanisms involved in the control of viral replication in individuals homozygous for this MAVS genotype. We observed that individuals with the MAVS minor genotype had more stable total CD4+ T cell counts during a 7-year follow up and had lower cell-associated proviral DNA loads. Genetic variation in MAVS did not affect immune activation levels; however, a significantly lower percentage of naïve CD4+ but not CD8+ T cells was observed in the MAVS minor genotype. In vitro HIV-1 infection of peripheral blood mononuclear cells (PBMCs) from healthy donors with the MAVS minor genotype resulted in decreased viral replication. Although the precise underlying mechanism remains unclear, our data suggest that the protective effect of the MAVS minor genotype may be exerted by the initiation of local innate responses affecting viral replication and CD4+ T cell susceptibility.

scholarly journals Immunological Differences in Human Peripheral Blood Mononuclear Cells Treated with Traditional Japanese Herbal Medicines Hochuekkito, Juzentaihoto, and Ninjin’yoeito from Different Pharmaceutical Companies

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Anna Kiyomi ◽  
Ayaka Matsuda ◽  
Moeko Nara ◽  
Kyosuke Yamazaki ◽  
Shinobu Imai ◽  
...  
Keyword(s):  
T Cell ◽  
Peripheral Blood Mononuclear Cells ◽  
Mononuclear Cells ◽  
Herbal Medicines ◽  
Cd4 T Cell ◽  
Pharmaceutical Companies ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Hochuekkito (HET), Juzentaihoto (JTT), and Ninjin’yoeito (NYT) have been used as Hozai, a group of traditional Japanese herbal medicines, to treat physically and mentally weak cancer patients. Their compositions are quite different, and Japanese pharmaceutical companies have been using different types or quantities of herbs for formulations with the same name. Here, we compared the immunological differences between HET, JTT, and NYT with respect to the induced T cell subsets and cytokines. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers and treated with 0 (control), 25, 50, 100, 200, or 400 μg/mL HET, JTT, or NYT (manufactured by Tsumura [TJ], Kracie [KR], and Kotaro [KO]). PBMC proliferation, CD4+ T cell, CD8+ T cell, and regulatory T cell (Treg) proportions and interleukin (IL) concentrations (IL-6, IL-10, IL-17A, interferon-γ, tumor necrosis factor-α, and transforming growth factor (TGF)-β) secreted by PBMCs were measured using Cell Counting Kit-8 or flow cytometry bead analysis. PBMC proliferation and CD4+ T cell percentages were similar in the HET, JTT, NYT, and control groups; however, the percentage of CD8+ T cells tended to increase after treatments. Tregs were suppressed by HET, JTT, and NYT, and TJ-JTT significantly decreased Treg numbers (compared with control). The concentrations of all cytokines except TGF-β were increased in a concentration-dependent manner ( p < 0.05 ); particularly, KR-HET induced IL-6 secretion (compared with the control, TJ-HET, and KO-HET; 37-, 7-, and 17-fold, respectively; p < 0.05 ). The TGF-β concentration was decreased in a concentration-dependent manner by HET, JTT, and NYT (compared with the control). These results suggest that, compared with TJ-HET and KO-HET, KR-HET should be administered with caution. Although HET, JTT, and NYT belong to the same Hozai group and have the same names among companies, their differing effects on immune activity must be considered and they must be administered with caution.

scholarly journals Neoadjuvant PROSTVAC prior to radical prostatectomy enhances T-cell infiltration into the tumor immune microenvironment in men with prostate cancer

2020 ◽  
Vol 8 (1) ◽  
pp. e000655 ◽  
Author(s):  
Houssein Abdul Sater ◽  
Jennifer L Marté ◽  
Renee N Donahue ◽  
Beatriz Walter-Rodriguez ◽  
Christopher R Heery ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune Response ◽  
T Cell ◽  
Radical Prostatectomy ◽  
Mononuclear Cells ◽  
Intracellular Cytokine Staining ◽  
Specific Antigen ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Cell Immunity

BackgroundClinical trials have shown the ability of therapeutic vaccines to generate immune responses to tumor-associated antigens (TAAs). What is relatively less known is if this translates into immune-cell (IC) infiltration into the tumor microenvironment. This study examined whether neoadjuvant prostate-specific antigen (PSA)-targeted vaccination with PROSTVAC could induce T-cell immunity, particularly at the tumor site.MethodsAn open-label, phase II study of neoadjuvant PROSTVAC vaccine enrolled 27 patients with localized prostate cancer awaiting radical prostatectomy (RP). We evaluated increases in CD4 and CD8 T-cell infiltrates (RP tissue vs baseline biopsies) using a six-color multiplex immunofluorescence Opal method. Antigen-specific responses were assessed by intracellular cytokine staining after in vitro stimulation of peripheral blood mononuclear cells with overlapping 15-mer peptide pools encoding the TAAs PSA, brachyury and MUC-1.ResultsOf 27 vaccinated patients, 26 had matched prevaccination (biopsy) and postvaccination (RP) prostate samples available for non-compartmentalized analysis (NCA) and compartmentalized analysis (CA). Tumor CD4 T-cell infiltrates were significantly increased in postvaccination RP specimens compared with baseline biopsies by NCA (median 176/mm² vs 152/mm²; IQR 136–317/mm² vs 69–284/mm²; p=0.0249; median ratio 1.20; IQR 0.64–2.25). By CA, an increase in both CD4 T-cell infiltrates at the tumor infiltrative margin (median 198/mm² vs 151/mm²; IQR 123–500/mm² vs 85–256/mm²; p=0.042; median ratio 1.44; IQR 0.59–4.17) and in CD8 T-cell infiltrates at the tumor core (median 140/mm² vs 105/mm²; IQR 91–175/mm² vs 83–163/mm²; p=0.036; median ratio 1.25; IQR 0.88–2.09) were noted in postvaccination RP specimens compared with baseline biopsies. A total of 13/25 patients (52%) developed peripheral T-cell responses to any of the three tested TAAs (non-neoantigens); five of these had responses to more than one antigen of the three evaluated.ConclusionNeoadjuvant PROSTVAC can induce both tumor immune response and peripheral immune response.Trial registration numberNCT02153918.

scholarly journals Characterization of CD4+ T Cell Subsets in Patients with Abdominal Aortic Aneurysms

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Fábio Haach Téo ◽  
Rômulo Tadeu Dias de Oliveira ◽  
Liana Villarejos ◽  
Ronei Luciano Mamoni ◽  
Albina Altemani ◽  
...  
Keyword(s):  
T Cell ◽  
Mononuclear Cells ◽  
Aortic Aneurysms ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Peripheral Blood Mononuclear ◽  
Abdominal Aortic ◽  
Tissue Degradation

Background. The mediators produced by CD4+ T lymphocytes are involved in the pathogenesis of aneurysmal lesions in abdominal aortic aneurysm (AAA) patients. The aim of this study was to identify and characterize the CD4+ T cell subsets involved in human AAA. Methods. The CD4+ T cell subsets in 30 human aneurysmal lesions were determined using flow cytometry (FC) and immunohistochemistry (IHC). The peripheral blood mononuclear cells (PBMCs) from patients with AAA were also analyzed by FC and compared with control subjects. Results. Human aneurysmal lesions contained IFN-γ, IL-12p35, IL-4, IL-23p19, IL-17R, and IL-22 positive cells. PBMCs from AAA patients had higher expression levels of IFN-γ, TNF-α, IL-4, and IL-22 when compared to controls. Conclusions. Our results show the presence of TH1, TH2, TH17, and TH22 subsets in aneurysmal lesions of AAA patients and suggest that these cells may be mainly activated in situ, where they can induce tissue degradation and contribute to the pathogenesis of AAA.

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