scholarly journals Zap70 Regulates TCR-Mediated Zip6 Activation at the Immunological Synapse

2021 ◽  
Vol 12 ◽  
Author(s):  
Bonah Kim ◽  
Hee Young Kim ◽  
Won-Woo Lee
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immunological Synapse ◽  
T Cell Responses ◽  
Confocal Imaging ◽  
Physical Interaction ◽  
Dependent Manner ◽  
Cell Responses ◽  
Zip Transporters ◽  
Tcr Activation

The essential microelement zinc plays immunoregulatory roles via its ability to influence signaling pathways. Zinc deficiency impairs overall immune function and resultantly increases susceptibility to infection. Thus, zinc is considered as an immune-boosting supplement for populations with hypozincemia at high-risk for infection. Besides its role as a structural cofactor of many proteins, zinc also acts as an intracellular messenger in immune cell signaling. T-cell activation instructs zinc influx from extracellular and subcellular sources through the Zip6 and Zip8 zinc transporters, respectively. Increased cytoplasmic zinc participates in the regulation of T-cell responses by modifying activation signaling. However, the mechanism underlying the activation-dependent movement of zinc ions by Zip transporters in T cells remains elusive. Here, we demonstrate that Zip6, one of the most abundantly expressed Zip transporters in T cells, is mainly localized to lipid rafts in human T cells and is recruited into the immunological synapse in response to TCR stimulation. This was demonstrated through confocal imaging of the interaction between CD4+ T cells and antigen-presenting cells. Further, immunoprecipitation assays show that TCR triggering induces tyrosine phosphorylation of Zip6, which has at least three putative tyrosine motifs in its long cytoplasmic region, and this phosphorylation is coupled with its physical interaction with Zap70. Silencing Zip6 reduces zinc influx from extracellular sources and suppresses T-cell responses, suggesting an interaction between Zip6-mediated zinc influx and TCR activation. These results provide new insights into the mechanism through which Zip6-mediated zinc influx occurs in a TCR activation-dependent manner in human CD4+ T cells.

scholarly journals Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell–mediated deletion

2012 ◽  
Vol 210 (1) ◽  
pp. 99-114 ◽  
Author(s):  
Dimitra Peppa ◽  
Upkar S. Gill ◽  
Gary Reynolds ◽  
Nicholas J.W. Easom ◽  
Laura J. Pallett ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hepatitis B ◽  
Nk Cells ◽  
Human Liver ◽  
Large Population ◽  
Death Receptor ◽  
T Cell Responses ◽  
Dependent Manner ◽  
Cell Responses

Antiviral T cell responses in hepatotropic viral infections such as hepatitis B virus (HBV) are profoundly diminished and prone to apoptotic deletion. In this study, we investigate whether the large population of activated NK cells in the human liver contributes to this process. We show that in vitro removal of NK cells augments circulating CD8+ T cell responses directed against HBV, but not against well-controlled viruses, in patients with chronic hepatitis B (CHB). We find that NK cells can rapidly eliminate HBV-specific T cells in a contact-dependent manner. CD8+ T cells in the liver microcirculation are visualized making intimate contact with NK cells, which are the main intrahepatic lymphocytes expressing TNF-related apoptosis-inducing ligand (TRAIL) in CHB. High-level expression of the TRAIL death receptor TRAIL-R2 is found to be a hallmark of T cells exposed to the milieu of the HBV-infected liver in patients with active disease. Up-regulation of TRAIL-R2 renders T cells susceptible to caspase-8–mediated apoptosis, from which they can be partially rescued by blockade of this death receptor pathway. Our findings demonstrate that NK cells can negatively regulate antiviral immunity in chronic HBV infection and illustrate a novel mechanism of T cell tolerance in the human liver.

scholarly journals CpG and Interleukin-15 Synergize to Enhance IFN-γ Production by Activated CD8+T Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Dustin Cobb ◽  
Siqi Guo ◽  
Ronald B. Smeltz
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Dependent Manner ◽  
Infectious Agents ◽  
Cell Responses ◽  
Striking Increase ◽  
Physiological Relevance ◽  
Interleukin 15 ◽  
Ifn Γ

Interleukin-15 (IL-15) regulates the development and maintenance of memory CD8+T cells. Paradoxically, we previously reported that IL-15 could enhance CD8+T-cell responses to IL-12, a proinflammatory cytokine required for optimal priming of effector CD8+T cells. To expand the physiological relevance of these findings, we tested IL-15 for its ability to enhance T-cell responses to bacterial CpG. Expectedly, CpG enhanced the production of IFN-γby CD8+T cells polyclonally activated with anti-CD3. However, addition of IL-15 to CpG-stimulated cultures led to a striking increase in IFN-γproduction. The effect of CpG and IL-15 was also evident with CD8+T cells recovered from mice infected with the parasiteTrypanosoma cruzi(T. cruzi) and restimulated with antigen. The observed synergy between CpG and IL-15 occurred in an IL-12-dependent manner, and this effect could even be demonstrated in cocultures of activated CD8+T cells and CD4+CD25+regulatory T cells. Although IFN-γwas not essential for CpG-induced IL-12, the ability of CpG and IL-15 to act on CD8+T cells required expression of the IFN-γ-inducible transcription factor T-bet. These data have important implications for development of vaccines and design of therapies to boost CD8+T-cell responses to infectious agents and tumors.

scholarly journals Perfect adaptation of CD8+ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation

2019 ◽  
Author(s):  
Nicola Trendel ◽  
Philipp Kruger ◽  
Stephanie Gaglione ◽  
John Nguyen ◽  
Johannes Pettmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytokine Production ◽  
Mechanistic Model ◽  
T Cell Responses ◽  
Dependent Manner ◽  
Antigen Stimulation ◽  
Cell Responses ◽  
Perfect Adaptation ◽  
Wide Range

AbstractMaintaining and limiting T cell responses to constant antigen stimulation is critical to control pathogens and maintain self-tolerance, respectively. Antigen recognition by T cell receptors (TCRs) induces signalling that activates T cells to produce cytokines and also leads to the downregulation of surface TCRs. In other systems, receptor downregulation can induce perfect adaptation to constant stimulation by a mechanism known as state-dependent inactivation that requires complete downregulation of the receptor or the ligand. However, this is not the case for the TCR, and therefore, precisely how TCR downregulation maintains or limits T cell responses is controversial. Here, we observed that in vitro expanded primary human T cells exhibit perfect adaptation in cytokine production to constant antigen stimulation across a 100,000-fold variation in affinity with partial TCR downregulation. By directly fitting a mechanistic model to the data, we show that TCR downregulation produces imperfect adaptation, but when coupled to a switch produces perfect adaptation in cytokine production. A pre-diction of the model is that pMHC-induced TCR signalling continues after adaptation and this is confirmed by showing that, while costimulation cannot prevent adaptation, CD28 and 4-1BB signalling reactivated adapted T cells to produce cytokines in a pMHC-dependent manner. We show that adaptation also applied to 1st generation chimeric antigen receptor (CAR)-T cells but is partially avoided in 2nd generation CARs. These findings high-light that even partial TCR downregulation can limit T cell responses by producing perfect adaptation rendering T cells dependent on costimulation for sustained responses.

scholarly journals Peptides Derived From S and N Proteins of Severe Acute Respiratory Syndrome Coronavirus 2 Induce T Cell Responses: A Proof of Concept for T Cell Vaccines

2021 ◽  
Vol 12 ◽  
Author(s):  
Yu-Sun Lee ◽  
So-Hee Hong ◽  
Hyo-Jung Park ◽  
Ho-Young Lee ◽  
Ji-Yeon Hwang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Severe Acute Respiratory Syndrome ◽  
T Cell Responses ◽  
Effector Memory ◽  
Target Cells ◽  
Dependent Manner ◽  
Peptide Vaccines ◽  
Cell Responses ◽  
Ifn Γ

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that escape vaccine-induced neutralizing antibodies has indicated the importance of T cell responses against this virus. In this study, we highlight the SARS-CoV-2 epitopes that induce potent T cell responses and discuss whether T cell responses alone are adequate to confer protection against SARS-CoV-2 and describe the administration of 20 peptides with an RNA adjuvant in mice. The peptides have been synthesized based on SARS-CoV-2 spike and nucleocapsid protein sequences. Our study demonstrates that immunization with these peptides significantly increases the proportion of effector memory T cell population and interferon-γ (IFN-γ)-, interleukin-4 (IL-4)-, tumor necrosis factor-α (TNF-α)-, and granzyme B-producing T cells. Of these 20 peptides, four induce the generation of IFN-γ-producing T cells, elicit CD8+ T cell (CTL) responses in a dose-dependent manner, and induce cytotoxic T lymphocytes that eliminate peptide-pulsed target cells in vivo. Although it is not statistically significant, these peptide vaccines reduce viral titers in infected hamsters and alleviate pulmonary pathology in SARS-CoV-2-infected human ACE2 transgenic mice. These findings may aid the design of effective SARS-CoV-2 peptide vaccines, while providing insights into the role of T cells in SARS-CoV-2 infection.

scholarly journals Immune Responses in Perforin Deficient Mice

2021 ◽  
Author(s):  
◽  
Helen Mary Alys Simkins
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Influenza Infection ◽  
T Cell Responses ◽  
Nkt Cells ◽  
T Cell Response ◽  
Dependent Manner ◽  
Cell Responses

<p>Dendritic cells (DC) play a pivotal role in the initiation of T cell responses and earlier studies have shown that their survival is important for the generation of effective immune responses. Cytotoxic T lymphocytes (CTL) and natural killer T (NKT) cells have been proposed to regulate the survival of antigen presenting DC through their ability to kill cells expressing specific antigen via secretion of perforin, a protein contained in cytotoxic granules. Perforin knockout (PKO) mice generate amplified immune responses to DC immunization, suggesting a link between defective cytotoxicity and increased T cell responses. The studies in this thesis used PKO mice and in vivo models of CD8+T cells and NKT cell immune responses to determine whether CTL and NKT cells eliminate DC in a perforin-dependent manner, and whether DC elimination is a mechanism to regulate T cell responses. During a primary influenza infection C57BL/6 and PKO mice generated a similar influenza specific CD8+ immune response. No significant difference in the percentage of influenza epitope PA224-233 specific T cells was observed between C57BL/6 and PKO mice during a secondary influenza infection, but PKO mice had a significantly reduced T cell response directed towards the dominant influenza epitope, NP366-374. The reduced T cell response in PKO mice was not due to differences in activation or differentiation status of specific T cells compared to C57BL/6 mice. Therefore, the extended DC survival in PKO after secondary influenza viral infection, recently reported by other authors, does not appear to correlate with increased expansion of virus specific CD8+T cells in infected mice. The role of NKT cells in DC elimination was assessed in vivo using the NKT cell ligand a-Galactosylceramide (a-GalCer). Injection of a-GalCer in C57BL/6 mice induced a dramatic decline in the number of splenic CD8+DC. A similar decrease in CD8+DC numbers was observed in PKO mice, suggesting that the mechanism of DC loss did not involve perforinmediated killing. In contrast, treatment with a TNF-a neutralizing antibody substantially reduced the decline in CD8+DC numbers. This reduction in splenic CD8+DC occurred as early as 15 hr after a-GalCer treatment, and did not affect generation of CD8+T cell responses or the ability of a-GalCer treatment to provide tumour protection. Taken together, these results suggest that multiple cells and mechanisms can regulate DC survival in vivo. CTL regulate DC survival in vivo in a perforin-dependent manner, but this does not necessarily affect the magnitude of the resulting immune responses. NKT cells also affect the survival of DC in vivo, but in a perforin-independent, cytokine-dependent manner. These findings provide additional knowledge about the in vivo involvement of perforin in regulating DC survival by CTL and NKT cells and the effects this has on T cell responses.</p>

scholarly journals Immune Responses in Perforin Deficient Mice

2021 ◽  
Author(s):  
◽  
Helen Mary Alys Simkins
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Influenza Infection ◽  
T Cell Responses ◽  
Nkt Cells ◽  
T Cell Response ◽  
Dependent Manner ◽  
Cell Responses

<p>Dendritic cells (DC) play a pivotal role in the initiation of T cell responses and earlier studies have shown that their survival is important for the generation of effective immune responses. Cytotoxic T lymphocytes (CTL) and natural killer T (NKT) cells have been proposed to regulate the survival of antigen presenting DC through their ability to kill cells expressing specific antigen via secretion of perforin, a protein contained in cytotoxic granules. Perforin knockout (PKO) mice generate amplified immune responses to DC immunization, suggesting a link between defective cytotoxicity and increased T cell responses. The studies in this thesis used PKO mice and in vivo models of CD8+T cells and NKT cell immune responses to determine whether CTL and NKT cells eliminate DC in a perforin-dependent manner, and whether DC elimination is a mechanism to regulate T cell responses. During a primary influenza infection C57BL/6 and PKO mice generated a similar influenza specific CD8+ immune response. No significant difference in the percentage of influenza epitope PA224-233 specific T cells was observed between C57BL/6 and PKO mice during a secondary influenza infection, but PKO mice had a significantly reduced T cell response directed towards the dominant influenza epitope, NP366-374. The reduced T cell response in PKO mice was not due to differences in activation or differentiation status of specific T cells compared to C57BL/6 mice. Therefore, the extended DC survival in PKO after secondary influenza viral infection, recently reported by other authors, does not appear to correlate with increased expansion of virus specific CD8+T cells in infected mice. The role of NKT cells in DC elimination was assessed in vivo using the NKT cell ligand a-Galactosylceramide (a-GalCer). Injection of a-GalCer in C57BL/6 mice induced a dramatic decline in the number of splenic CD8+DC. A similar decrease in CD8+DC numbers was observed in PKO mice, suggesting that the mechanism of DC loss did not involve perforinmediated killing. In contrast, treatment with a TNF-a neutralizing antibody substantially reduced the decline in CD8+DC numbers. This reduction in splenic CD8+DC occurred as early as 15 hr after a-GalCer treatment, and did not affect generation of CD8+T cell responses or the ability of a-GalCer treatment to provide tumour protection. Taken together, these results suggest that multiple cells and mechanisms can regulate DC survival in vivo. CTL regulate DC survival in vivo in a perforin-dependent manner, but this does not necessarily affect the magnitude of the resulting immune responses. NKT cells also affect the survival of DC in vivo, but in a perforin-independent, cytokine-dependent manner. These findings provide additional knowledge about the in vivo involvement of perforin in regulating DC survival by CTL and NKT cells and the effects this has on T cell responses.</p>

scholarly journals Adenoviral vaccines promote protective tissue-resident memory T cell populations against cancer

2020 ◽  
Vol 8 (2) ◽  
pp. e001133
Author(s):  
Esmé TI van der Gracht ◽  
Mark JA Schoonderwoerd ◽  
Suzanne van Duikeren ◽  
Ayse N Yilmaz ◽  
Felix M Behr ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Adenoviral Vectors ◽  
Cell Populations ◽  
Dependent Manner ◽  
Cell Responses ◽  
Specific Memory ◽  
Tumor Protection

BackgroundAdenoviral vectors emerged as important platforms for cancer immunotherapy. Vaccination with adenoviral vectors is promising in this respect, however, their specific mechanisms of action are not fully understood. Here, we assessed the development and maintenance of vaccine-induced tumor-specific CD8+ T cells elicited upon immunization with adenoviral vectors.MethodsAdenoviral vaccine vectors encoding the full-length E7 protein from human papilloma virus (HPV) or the immunodominant epitope from E7 were generated, and mice were immunized intravenously with different quantities (107, 108 or 109 infectious units). The magnitude, kinetics and tumor protection capacity of the induced vaccine-specific T cell responses were evaluated.ResultsThe adenoviral vaccines elicited inflationary E7-specific memory CD8+ T cell responses in a dose-dependent manner. The magnitude of these vaccine-specific CD8+ T cells in the circulation related to the development of E7-specific CD8+ tissue-resident memory T (TRM) cells, which were maintained for months in multiple tissues after vaccination. The vaccine-specific CD8+ T cell responses conferred long-term protection against HPV-induced carcinomas in the skin and liver, and this protection required the induction and accumulation of CD8+ TRM cells. Moreover, the formation of CD8+ TRM cells could be enhanced by temporal targeting CD80/CD86 costimulatory interactions via CTLA-4 blockade early after immunization.ConclusionsTogether, these data show that adenoviral vector-induced CD8+ T cell inflation promotes protective TRM cell populations, and this can be enhanced by targeting CTLA-4.

scholarly journals Helicobacter pylori-induced adrenomedullin modulates IFN-γ-producing T-cell responses and contribute to gastritis

2018 ◽  
Author(s):  
Hui Kong ◽  
Jin-yu Zhang ◽  
Fang-yuan Mao ◽  
Yong-sheng Teng ◽  
Yi-pin Lv ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gastric Mucosa ◽  
Epithelial Cells ◽  
T Cell Responses ◽  
Dependent Manner ◽  
Gastric Epithelial Cells ◽  
Cell Responses ◽  
Ifn Γ ◽  
H Pylori

AbstractAdrenomedullin (ADM) is a multifunctional peptide that is expressed by many surface epithelial cells, but its relevance to H. pylori-induced gastritis is unknown. Here, we found that gastric ADM expression was elevated in gastric mucosa of H. pylori-infected patients and mice. In H. pylori-infected human gastric mucosa, ADM expression was positively correlated with the degree of gastritis, accordingly, blockade of ADM resulted in decreased inflammation within the gastric mucosa of H. pylori-infected mice. During H. pylori infection, ADM production was promoted via PI3K-AKT signaling pathway activation by gastric epithelial cells in a cagA-dependent manner, and resulted in increased inflammation within the gastric mucosa. This inflammation was characterized by the increased IFN-γ-producing T cells, whose differentiation was induced via the phosphorylation of AKT and STAT3 by ADM derived from gastric epithelial cells. ADM also induced macrophages to produce IL-12, which promoted the IFN-γ-producing T-cell responses, thereby contributing to the development of H. pylori-associated gastritis. Accordingly, blockade of IFN-γ or knockout of IFN-γ decreased inflammation within the gastric mucosa of H. pylori-infected mice. This study identifies a novel regulatory network involving H. pylori, gastric epithelial cells, ADM, macrophages, T cells, and IFN-γ, which collectively exert a pro-inflammatory effect within the gastric microenvironment.Author summaryH. pylori infect almost half the world’s population. Once infected, most of people carry the bacteria lifelong if left untreated, so that persistent H. pylori infection can lead to chronic gastritis, peptic ulceration and ultimately gastric cancer. H. pylori infection is accompanied with increased inflammation in gastric mucosa, but the mechanisms of chronic gastritis induced by H. pylori infection remains poorly understood. We studied a multifunctional peptide known as adrenomedullin (ADM) in gastric epithelial cells, which was known as a key factor of regulating gastrointestinal physiology and pathology. Here, we found that gastric ADM expression was elevated in gastric mucosa of H. pylori-infected patients and mice, and was positively correlated with the degree of gastritis. ADM production was promoted via PI3K-AKT signaling pathway activation by gastric epithelial cells in a cagA-dependent manner. Blockade of ADM during H. pylori infection resulted in decreased gastric inflammation that was characterized by the increased IFN-γ-producing T cells which was induced via the phosphorylation of AKT and STAT3 by ADM derived from gastric epithelial cells. ADM also induced macrophages to produce IL-12, which promoted the IFN-γ-producing T-cell responses. These data demonstrate that H. pylori-induced ADM modulates FN-γ-producing T-cell responses and contribute to gastritis.

scholarly journals Cytokines regulate the antigen-presenting characteristics of human circulating and tissue-resident intestinal ILCs

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Anna Rao ◽  
Otto Strauss ◽  
Efthymia Kokkinou ◽  
Mélanie Bruchard ◽  
Kumar P. Tripathi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Cancer Tissue ◽  
Dependent Manner ◽  
Cell Responses ◽  
Specific Memory ◽  
Hla Dr ◽  
Antigen Presenting

AbstractILCs and T helper cells have been shown to exert bi-directional regulation in mice. However, how crosstalk between ILCs and CD4+ T cells influences immune function in humans is unknown. Here we show that human intestinal ILCs co-localize with T cells in healthy and colorectal cancer tissue and display elevated HLA-DR expression in tumor and tumor-adjacent areas. Although mostly lacking co-stimulatory molecules ex vivo, intestinal and peripheral blood (PB) ILCs acquire antigen-presenting characteristics triggered by inflammasome-associated cytokines IL-1β and IL-18. IL-1β drives the expression of HLA-DR and co-stimulatory molecules on PB ILCs in an NF-κB-dependent manner, priming them as efficient inducers of cytomegalovirus-specific memory CD4+ T-cell responses. This effect is strongly inhibited by the anti-inflammatory cytokine TGF-β. Our results suggest that circulating and tissue-resident ILCs have the intrinsic capacity to respond to the immediate cytokine milieu and regulate local CD4+ T-cell responses, with potential implications for anti-tumor immunity and inflammation.

scholarly journals Topical CpG Adjuvantation of a Protein-Based Vaccine Induces Protective Immunity to Listeria monocytogenes

2014 ◽  
Vol 21 (3) ◽  
pp. 329-339 ◽  
Author(s):  
Wing Ki Cheng ◽  
Kathleen Wee ◽  
Tobias R. Kollmann ◽  
Jan P. Dutz
Keyword(s):  
T Cells ◽  
Listeria Monocytogenes ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Parenteral Administration ◽  
Effector Memory ◽  
Dependent Manner ◽  
Content Type ◽  
Cell Responses

ABSTRACTRobust CD8+T cell responses are essential for immune protection against intracellular pathogens. Using parenteral administration of ovalbumin (OVA) protein as a model antigen, the effect of the Toll-like receptor 9 (TLR9) agonist, CpG oligodeoxynucleotide (ODN) 1826, as an adjuvant delivered either topically, subcutaneously, or intramuscularly on antigen-specific CD8+T cell responses in a mouse model was evaluated. Topical CpG adjuvant increased the frequency of OVA-specific CD8+T cells in the peripheral blood and in the spleen. The more effective strategy to administer topical CpG adjuvant to enhance CD8+T cell responses was single-dose administration at the time of antigen injection with a prime-boost regimen. Topical CpG adjuvant conferred both rapid and long-lasting protection against systemic challenge with recombinantListeria monocytogenesexpressing the cytotoxic T lymphocyte (CTL) epitope of OVA257–264(strainLm-OVA) in a TLR9-dependent manner. Topical CpG adjuvant induced a higher proportion of CD8+effector memory T cells than parenteral administration of the adjuvant. Although traditional vaccination strategies involve coformulation of antigen and adjuvant, split administration using topical adjuvant is effective and has advantages of safety and flexibility. Split administration of topical CpG ODN 1826 with parenteral protein antigen is superior to other administration strategies in enhancing both acute and memory protective CD8+T cell immune responses to subcutaneous protein vaccines. This vaccination strategy induces rapid and persistent protective immune responses against the intracellular organismL. monocytogenes.

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