Study of T-cell activation in Type I diabetic patients and pre-Type I diabetic subjects by cytometric analysis: Antigen expression defectin vitro

e14306 Background: Even with curative resection, the recurrence rate of HCC is still high, and no effective adjuvant therapy is currently available. Our previous Phase I study with novel therapeutic peptides and immune adjuvants demonstrated the safety, antigen specific CTL induction in PBMC and a sign of efficacy (ASCO 2017 Abstract # 3086); thus, we started Phase I study of the same therapy as a perioperative immunotherapy setting in patients with resectable HCC (UMIN000029991). Methods: Two mg each of HLA-A*24:02, 02:01, or 02:06 restricted HSP70- and GPC3-derived peptides, in combination with hLAG-3Ig (1.0 mg) + Poly-IC:LC (1.4 mg) were injected intradermally at four sites of the inguinal and axillary regions every week for 6 weeks before surgery. Patients subsequently received 10 injections of adjuvant immunotherapy over 4 months. Surgical specimens and PBMCs were analyzed by mass cytometry (CyTOF), using 66 antibodies to monitor T cell exhaustion, T cell activation, Effector Treg induction, etc. Tumor specimens were also subjected to immunohistochemical staining of CD3, CD8, PD1, HSP70, and GPC3. The reason for early reporting is the interesting findings at the foci of HCC, and the interim analyses was approved by the Data and Safety Monitoring Committee. Results: Of the 11 screened patients, 5 completed the treatments and were analyzed. We found massive CD8+ T lymphocyte infiltration in the intratumor foci of HCC, which is usually accompanied by peritumoral lymphocytic infiltration. Moreover, the density of lymphocytes was markedly higher in areas of HSP70 or GPC3 antigen expression. One case out of five recurred 5 month after surgery and it showed low CD8+ and PD1+ cell infiltration and high effector Treg (CD4+/CD25+/CD45RA-/FoxP3 +) infiltration. This trend was not observed in PBMC, suggesting the importance of TIL analysis. The high PD1 expression was accompanied by massive intratumoral infiltration of CD8+ lymphocytes. Conclusions: The novel therapeutic peptide and immune adjuvant combination induced sustained immune cell infiltration into tumor microenvironments, especially those presenting target tumor-associated antigens. Our novel immunotherapy may convert cold tumors into hot tumors containing PD1+ lymphocytes. Thus, the combination of this novel strategy with PD (L) 1 antibody is warranted. Clinical trial information: 000029991.

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Type I Interferon-mediated Stimulation of T Cells by CpG DNA

Journal of Experimental Medicine ◽

10.1084/jem.188.12.2335 ◽

1998 ◽

Vol 188 (12) ◽

pp. 2335-2342 ◽

Cited By ~ 271

Author(s):

Siquan Sun ◽

Xiaohong Zhang ◽

David F. Tough ◽

Jonathan Sprent

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Type I Interferons ◽

Type I ◽

Cpg Dna ◽

Stimulation Of

Immunostimulatory DNA and oligodeoxynucleotides containing unmethylated CpG motifs (CpG DNA) are strongly stimulatory for B cells and antigen-presenting cells (APCs). We report here that, as manifested by CD69 and B7-2 upregulation, CpG DNA also induces partial activation of T cells, including naive-phenotype T cells, both in vivo and in vitro. Under in vitro conditions, CpG DNA caused activation of T cells in spleen cell suspensions but failed to stimulate highly purified T cells unless these cells were supplemented with APCs. Three lines of evidence suggested that APC-dependent stimulation of T cells by CpG DNA was mediated by type I interferons (IFN-I). First, T cell activation by CpG DNA was undetectable in IFN-IR−/− mice. Second, in contrast to normal T cells, the failure of purified IFN-IR−/− T cells to respond to CpG DNA could not be overcome by adding normal IFN-IR+ APCs. Third, IFN-I (but not IFN-γ) caused the same pattern of partial T cell activation as CpG DNA. Significantly, T cell activation by IFN-I was APC independent. Thus, CpG DNA appeared to stimulate T cells by inducing APCs to synthesize IFN-I, which then acted directly on T cells via IFN-IR. Functional studies suggested that activation of T cells by IFN-I was inhibitory. Thus, exposing normal (but not IFN-IR−/−) T cells to CpG DNA in vivo led to reduced T proliferative responses after TCR ligation in vitro.

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Age-Associated Failure To Adjust Type I IFN Receptor Signaling Thresholds after T Cell Activation

The Journal of Immunology ◽

10.4049/jimmunol.1402389 ◽

2015 ◽

Vol 195 (3) ◽

pp. 865-874 ◽

Cited By ~ 21

Author(s):

Guangjin Li ◽

Jihang Ju ◽

Cornelia M. Weyand ◽

Jörg J. Goronzy

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Type I ◽

Receptor Signaling ◽

Type I Ifn ◽

Signaling Thresholds

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Type I Interferon Signaling before Hematopoietic Stem Cell Transplantation Lowers Donor T Cell Activation Via Reduced Allogenicity of Recipient Cells

Blood ◽

10.1182/blood-2019-128784 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4431-4431

Author(s):

Erik Thiele Orberg ◽

Julius Clemens Fischer ◽

Sascha Göttert ◽

Florian Bassermann ◽

Hendrik Poeck

Keyword(s):

T Cells ◽

Stem Cell ◽

T Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

T Cell Activation ◽

Cell Activation ◽

Type I ◽

Hematopoietic Stem ◽

Conditioning Therapy

Background: Recent studies highlight immunoregulatory functions of type I interferons (IFN-I) during the pathogenesis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We demonstrated that selective activation of IFN-I pathways including RIG-I/MAVS and cGAS/STING prior to allo-HSCT conditioning therapy can ameliorate the course of GVHD. However, direct effects of IFN-Is on immune cells remain ill characterised. Methods: We applied selective RIG-I agonists (3pRNA) to stimulate IFN-I production in murine models of conditioning therapy with total body irradiation (TBI) and GVHD. Results: Using IFNAR1-deficient donor T and hematopoietic donor cells, we found that endogenous and RIG-I-induced IFN-Is do not reduce GVHD by acting on these respective cell types. However, 3pRNA applied before conditioning therapy reduced the ability of CD11c+ recipient cells to stimulate proliferation and interferon gamma expression of allogeneic T cells. Consistently, RIG-I activation before TBI reduced the proliferation of transplanted T-cells after allo-HSCT. The reduced allogenicity of CD11c+ recipient cells was dependent on IFN-I signalling. Notably, this immunosuppressive function of DCs was restricted to a scenario of genotoxic tissue damage as neither RIG-I activation and IFN-I induction in naive (non-irradiated) mice altered allogeneic T cell activation. Conclusion: Our findings uncover a hitherto unknown IFN-I- and context dependent immunosuppressive function of dendritic cells. This needs to be considered in the development of IFN-I based therapeutic approaches to modulate donor T cell activation after allo-HSCT. Disclosures No relevant conflicts of interest to declare.

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Discovery of Novel Inhibitors From Medicinal Plants for V-Domain Ig Suppressor of T-Cell Activation

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.716735 ◽

2021 ◽

Vol 8 ◽

Author(s):

Iqra Muneer ◽

Sajjad Ahmad ◽

Anam Naz ◽

Sumra Wajid Abbasi ◽

Adel Alblihy ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Transmembrane Protein ◽

Experimental Studies ◽

Binding Energies ◽

Type I ◽

Active Site Residues ◽

High Concentration ◽

Delay Tumor Growth

V-domain Ig suppressor of T cell activation (VISTA) is an immune checkpoint and is a type I transmembrane protein. VISTA is linked to immunotherapy resistance, and it is a potential immune therapeutic target, especially for triple-negative breast cancer. It expresses at a high concentration in regulatory T cells and myeloid-derived suppressor cells, and its functional blockade is found to delay tumor growth. A useful medicinal plant database for drug designing (MPD3), which is a collection of phytochemicals from diverse plant families, was employed in virtual screening against VISTA to prioritize natural inhibitors against VISTA. Three compounds, Paratocarpin K (PubChem ID: 14187087), 3-(1H-Indol-3-yl)-2-(trimethylazaniumyl)propanoate (PubChem ID: 3861164), and 2-[(5-Benzyl-4-ethyl-1,2,4-triazol-3-yl)sulfanylmethyl]-5-methyl-1,3,4-oxadiazole (PubChem ID: 6494266), having binding energies stronger than −6 kcal/mol were found to have two common hydrogen bond interactions with VISTA active site residues: Arg54 and Arg127. The dynamics of the compound–VISTA complexes were further explored to infer binding stability of the systems. Results revealed that the compound 14187087 and 6494266 systems are highly stable with an average RMSD of 1.31 Å. Further affirmation on the results was achieved by running MM-GBSA on the MD simulation trajectories, which re-ranked 14187087 as the top-binder with a net binding energy value of −33.33 kcal/mol. In conclusion, the present study successfully predicted natural compounds that have the potential to block the function of VISTA and therefore can be utilized further in experimental studies to validate their real anti-VISTA activity.

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Analysis of type I IFN response and T cell activation in severe COVID-19/HIV-1 coinfection: A case report: Erratum

Medicine ◽

10.1097/md.0000000000022949 ◽

2020 ◽

Vol 99 (42) ◽

pp. e22949

Keyword(s):

Case Report ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Type I ◽

Type I Ifn ◽

Hiv 1

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The gene for B7, a costimulatory signal for T-cell activation, maps to chromosomal region 3q13.3-3q21

Blood ◽

10.1182/blood.v79.2.489.489 ◽

1992 ◽

Vol 79 (2) ◽

pp. 489-494 ◽

Cited By ~ 20

Author(s):

GJ Freeman ◽

CM Disteche ◽

JG Gribben ◽

DA Adler ◽

AS Freedman ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Lymphocyte Activation ◽

Large Cell ◽

Chromosome 3 ◽

Type I ◽

Metaphase Chromosomes ◽

Angioimmunoblastic Lymphadenopathy ◽

Human T Cell

Abstract B7 is an activation antigen expressed on activated B cells and gamma- interferon-stimulated monocytes. The B7 antigen is the natural ligand for CD28 on T cells. After engagement of T-cell receptor with antigen in association with major histocompatibility complex class II, a second signal mediated through the binding of B7 to CD28 greatly upregulates the production of multiple lymphokines. We have now mapped the B7 gene to human chromosome 3 using the technique of polymerase chain reaction on a panel of hamster x human somatic cell hybrid DNAs. We have further localized the gene to 3q13.3–3q21 using in situ hybridization on human metaphase chromosomes. Trisomy of chromosome 3 is a recurrent chromosome change seen in various lymphomas and lymphoproliferative diseases, particularly diffuse, mixed, small, and large cell lymphomas, human T-cell lymphotropic virus type I-induced adult T-cell leukemia, and angioimmunoblastic lymphadenopathy. A number of chromosomal defects involving 3q21 have been described in acute myeloid leukemia and also in myelodysplastic and myeloproliferative syndromes. The mapping of B7 may permit further insight into disease states associated with aberrant lymphocyte activation and lymphokine synthesis.

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