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Article ; Online: STAT1 Controls the Functionality of Influenza-Primed CD4 T Cells but Therapeutic STAT4 Engagement Maximizes Their Antiviral Impact.

Finn, Caroline M / Dhume, Kunal / Prokop, Emily / Strutt, Tara M / McKinstry, K Kai

Journal of immunology (Baltimore, Md. : 1950)

2023 Volume 210, Issue 9, Page(s) 1292–1304

Abstract: It is generally accepted that influenza A virus (IAV) infection promotes a Th1-like CD4 T cell response and that this effector program underlies its protective impact. Canonical Th1 polarization requires cytokine-mediated activation of the transcription ... ...

Abstract	It is generally accepted that influenza A virus (IAV) infection promotes a Th1-like CD4 T cell response and that this effector program underlies its protective impact. Canonical Th1 polarization requires cytokine-mediated activation of the transcription factors STAT1 and STAT4 that synergize to maximize the induction of the "master regulator" Th1 transcription factor, T-bet. Here, we determine the individual requirements for these transcription factors in directing the Th1 imprint primed by influenza infection in mice by tracking virus-specific wild-type or T-bet-deficient CD4 T cells in which STAT1 or STAT4 is knocked out. We find that STAT1 is required to protect influenza-primed CD4 T cells from NK cell-mediated deletion and for their expression of hallmark Th1 attributes. STAT1 is also required to prevent type I IFN signals from inhibiting the induction of the Th17 master regulator, Rorγt, in Th17-prone T-bet-/- cells responding to IAV. In contrast, STAT4 expression does not appreciably impact the phenotypic or functional attributes of wild-type or T-bet-/- CD4 T cell responses. However, cytokine-mediated STAT4 activation in virus-specific CD4 T cells enhances their Th1 identity in a T-bet-dependent manner, indicating that influenza infection does not promote maximal Th1 induction. Finally, we show that the T-bet-dependent protective capacity of CD4 T cell effectors against IAV is optimized by engaging both STAT1 and STAT4 during Th1 priming, with important implications for vaccine strategies aiming to generate T cell immunity.
MeSH term(s)	Mice ; Animals ; Humans ; CD4-Positive T-Lymphocytes ; Antiviral Agents/metabolism ; Influenza, Human ; T-Box Domain Proteins/metabolism ; Interferon-gamma/metabolism ; Transcription Factors/metabolism ; Th1 Cells ; STAT4 Transcription Factor/metabolism ; Cell Differentiation ; STAT1 Transcription Factor/metabolism
Chemical Substances	Antiviral Agents ; T-Box Domain Proteins ; Interferon-gamma (82115-62-6) ; Transcription Factors ; STAT4 Transcription Factor ; Stat1 protein, mouse ; STAT1 Transcription Factor ; Stat4 protein, mouse
Language	English
Publishing date	2023-03-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2200407
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Article ; Online: The Regulation of Inflammation by Innate and Adaptive Lymphocytes.

Cronkite, David Alex / Strutt, Tara M

Journal of immunology research

2018 Volume 2018, Page(s) 1467538

Abstract: Inflammation plays an essential role in the control of pathogens and in shaping the ensuing adaptive immune responses. Traditionally, innate immunity has been described as a rapid response triggered through generic and nonspecific means that by ... ...

Abstract	Inflammation plays an essential role in the control of pathogens and in shaping the ensuing adaptive immune responses. Traditionally, innate immunity has been described as a rapid response triggered through generic and nonspecific means that by definition lacks the ability to remember. Recently, it has become clear that some innate immune cells are epigenetically reprogrammed or "imprinted" by past experiences. These "trained" innate immune cells display altered inflammatory responses upon subsequent pathogen encounter. Remembrance of past pathogen encounters has classically been attributed to cohorts of antigen-specific memory T and B cells following the resolution of infection. During recall responses, memory T and B cells quickly respond by proliferating, producing effector cytokines, and performing various effector functions. An often-overlooked effector function of memory CD4 and CD8 T cells is the promotion of an inflammatory milieu at the initial site of infection that mirrors the primary encounter. This memory-conditioned inflammatory response, in conjunction with other secondary effector T cell functions, results in better control and more rapid resolution of both infection and the associated tissue pathology. Recent advancements in our understanding of inflammatory triggers, imprinting of the innate immune responses, and the role of T cell memory in regulating inflammation are discussed.
MeSH term(s)	Adaptive Immunity ; Animals ; B-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/physiology ; CD8-Positive T-Lymphocytes/immunology ; Cytokines/metabolism ; Humans ; Immunity, Innate ; Immunologic Memory ; Inflammation/immunology ; Mice ; T-Lymphocytes/immunology ; Vaccination
Chemical Substances	Cytokines
Language	English
Publishing date	2018-06-11
Publishing country	Egypt
Document type	Journal Article ; Review
ZDB-ID	2817541-4
ISSN	2314-7156 ; 2314-8861
ISSN (online)	2314-7156
ISSN	2314-8861
DOI	10.1155/2018/1467538
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Article ; Online: Mouse Models Reveal Role of T-Cytotoxic and T-Reg Cells in Immune Response to Influenza: Implications for Vaccine Design.

Sell, Stewart / McKinstry, Karl Kai / Strutt, Tara M

Viruses

2019 Volume 11, Issue 1

Abstract: Immunopathologic examination of the lungs of mouse models of experimental influenza virus infection provides new insights into the immune response in this disease. First, there is rapidly developing perivascular and peribronchial infiltration of the lung ...

Abstract	Immunopathologic examination of the lungs of mouse models of experimental influenza virus infection provides new insights into the immune response in this disease. First, there is rapidly developing perivascular and peribronchial infiltration of the lung with T-cells. This is followed by invasion of T-cells into the bronchiolar epithelium, and separation of epithelial cells from each other and from the basement membrane leading to defoliation of the bronchial epithelium. The intraepithelial reaction may involve either CD8 or CD4 T-cytotoxic cells and is analogous to a viral exanthema of the skin, such as measles and smallpox, which occur when the immune response against these infections is activated and the infected cells are attacked by T-cytotoxic cells. Then there is formation of B-cell follicles adjacent to bronchi, i.e., induced bronchial associated lymphoid tissue (iBALT). iBALT reacts like the cortex of a lymph node and is a site for a local immune response not only to the original viral infection, but also related viral infections (heterologous immunity). Proliferation of Type II pneumocytes and/or terminal bronchial epithelial cells may extend into the adjacent lung leading to large zones filled with tumor-like epithelial cells. The effective killing of influenza virus infected epithelial cells by T-cytotoxic cells and induction of iBALT suggests that adding the induction of these components might greatly increase the efficacy of influenza vaccination.
MeSH term(s)	Animals ; Antibodies, Viral/blood ; Bronchi/cytology ; Bronchi/immunology ; Bronchi/virology ; Cell Proliferation ; Disease Models, Animal ; Drug Design ; Immunity, Mucosal ; Influenza Vaccines/immunology ; Mice ; Orthomyxoviridae ; Orthomyxoviridae Infections/immunology ; T-Lymphocytes, Cytotoxic/immunology ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Antibodies, Viral ; Influenza Vaccines
Language	English
Publishing date	2019-01-11
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v11010052
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Article ; Online: CD122-targetted IL-2 signals cause acute and selective apoptosis of B cells in Peyer's Patches.

Singh, Ayushi / Dhume, Kunal / Tejero, Joanne D / Strutt, Tara M / McKinstry, K Kai

Scientific reports

2020 Volume 10, Issue 1, Page(s) 12668

Abstract: Interleukin-2 (IL-2) has both pro- and anti-inflammatory properties that have been harnessed clinically and that are used experimentally to modulate leukocyte subsets in vivo. In mice, the bioavailability and half-life of IL-2 in vivo can be increased by ...

Abstract	Interleukin-2 (IL-2) has both pro- and anti-inflammatory properties that have been harnessed clinically and that are used experimentally to modulate leukocyte subsets in vivo. In mice, the bioavailability and half-life of IL-2 in vivo can be increased by complexing recombinant IL-2 with different clones of anti-IL-2 monoclonal antibodies that differentially target the cytokine to cells expressing different kinds of IL-2 receptors. While the impacts of systemic IL-2: anti-IL-2 antibody complex (IL-2C) administration are well-defined in the spleen and peripheral lymph nodes, how immune cells in the gut and gut-associated lymphoid tissues respond to IL-2C is not well characterized. Here, we analyze how major leukocyte populations in these tissues respond to IL-2C. We find that IL-2C targeting cells expressing IL-2 receptor beta cause an acute decrease in cellularity of Peyer's Patches while cell numbers in the lamina propria and intraepithelial lymphocytes are unaffected. Cell contraction in Peyer's Patches is associated with the apoptosis of multiple B cell subsets. Our results are important to consider for understanding off-target impacts of IL-2C regimes in experimental models and for considering how IL-2 may contribute to the etiology or severity of gut-associated conditions such as Crohn's Disease.
MeSH term(s)	Animals ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/pharmacology ; B-Lymphocytes/cytology ; B-Lymphocytes/drug effects ; B-Lymphocytes/metabolism ; Biological Availability ; Cell Survival/drug effects ; Complex Mixtures/administration & dosage ; Complex Mixtures/pharmacology ; Female ; Half-Life ; Interleukin-2/antagonists & inhibitors ; Interleukin-2/metabolism ; Interleukin-2 Receptor beta Subunit/metabolism ; Mice ; Peyer's Patches/cytology ; Peyer's Patches/drug effects ; Peyer's Patches/metabolism ; Recombinant Proteins/administration & dosage ; Recombinant Proteins/pharmacology
Chemical Substances	Antibodies, Monoclonal ; Complex Mixtures ; Il2rb protein, mouse ; Interleukin-2 ; Interleukin-2 Receptor beta Subunit ; Recombinant Proteins
Language	English
Publishing date	2020-07-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-69632-5
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Article ; Online: Intermediate Levels of Pre-Existing Protective Antibody Allow Priming of Protective T Cell Immunity against Influenza.

Ng, Terry / Flores-Malavet, Valeria / Mansoor, Mishfak A M / Arvelo, Andrea C / Dhume, Kunal / Prokop, Emily / McKinstry, K Kai / Strutt, Tara M

Journal of immunology (Baltimore, Md. : 1950)

2023 Volume 210, Issue 5, Page(s) 628–639

Abstract: Overcoming interfering impacts of pre-existing immunity to generate universally protective influenza A virus (IAV)-specific T cell immunity through vaccination is a high priority. In this study, we passively transfer varied amounts of H1N1-IAV-specific ... ...

Abstract	Overcoming interfering impacts of pre-existing immunity to generate universally protective influenza A virus (IAV)-specific T cell immunity through vaccination is a high priority. In this study, we passively transfer varied amounts of H1N1-IAV-specific immune serum before H1N1-IAV infection to determine how different levels of pre-existing Ab influence the generation and protective potential of heterosubtypic T cell responses in a murine model. Surprisingly, IAV nucleoprotein-specific CD4 and CD8 T cell responses are readily detected in infected recipients of IAV-specific immune serum regardless of the amount transferred. When compared with responses in control groups and recipients of low and intermediate levels of convalescent serum, nucleoprotein-specific T cell responses in recipients of high levels of IAV-specific serum, which prevent overt weight loss and reduce peak viral titers in the lungs, are, however, markedly reduced. Although detectable at priming, this response recalls poorly and is unable to mediate protection against a lethal heterotypic (H3N2) virus challenge at later memory time points. A similar failure to generate protective heterosubtypic T cell immunity during IAV priming is seen in offspring of IAV-primed mothers that naturally receive high titers of IAV-specific Ab through maternal transfer. Our findings support that priming of protective heterosubtypic T cell responses can occur in the presence of intermediate levels of pre-existing Ab. These results have high relevance to vaccine approaches aiming to incorporate and evaluate cellular and humoral immunity towards IAV and other viral pathogens against which T cells can protect against variants escaping Ab-mediated protection.
MeSH term(s)	Animals ; Mice ; Humans ; Influenza, Human ; Influenza A Virus, H3N2 Subtype ; Influenza A Virus, H1N1 Subtype ; Influenza Vaccines ; Influenza A virus ; CD8-Positive T-Lymphocytes ; Antibodies, Viral ; Immune Sera ; Orthomyxoviridae Infections
Chemical Substances	Influenza Vaccines ; Antibodies, Viral ; Immune Sera
Language	English
Publishing date	2023-01-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2200393
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Article ; Online: CD4 Effector TCR Avidity for Peptide on APC Determines the Level of Memory Generated.

Jones, Michael C / Castonguay, Catherine / Nanaware, Padma P / Weaver, Grant C / Stadinski, Brian / Kugler-Umana, Olivia A / Huseby, Eric S / Stern, Lawrence J / McKinstry, Karl Kai / Strutt, Tara M / Devarajan, Priyadharshini / Swain, Susan L

Journal of immunology (Baltimore, Md. : 1950)

2023 Volume 210, Issue 12, Page(s) 1950–1961

Abstract: Initial TCR affinity for peptide Ag is known to impact the generation of memory; however, its contributions later, when effectors must again recognize Ag at 5-8 d postinfection to become memory, is unclear. We examined whether the effector TCR affinity ... ...

Abstract	Initial TCR affinity for peptide Ag is known to impact the generation of memory; however, its contributions later, when effectors must again recognize Ag at 5-8 d postinfection to become memory, is unclear. We examined whether the effector TCR affinity for peptide at this "effector checkpoint" dictates the extent of memory and degree of protection against rechallenge. We made an influenza A virus nucleoprotein (NP)-specific TCR transgenic mouse strain, FluNP, and generated NP-peptide variants that are presented by MHC class II to bind to the FluNP TCR over a broad range of avidity. To evaluate the impact of avidity in vivo, we primed naive donor FluNP in influenza A virus-infected host mice, purified donor effectors at the checkpoint, and cotransferred them with the range of peptides pulsed on activated APCs into second uninfected hosts. Higher-avidity peptides yielded higher numbers of FluNP memory cells in spleen and most dramatically in lung and draining lymph nodes and induced better protection against lethal influenza infection. Avidity determined memory cell number, not cytokine profile, and already impacted donor cell number within several days of transfer. We previously found that autocrine IL-2 production at the checkpoint prevents default effector apoptosis and supports memory formation. Here, we find that peptide avidity determines the level of IL-2 produced by these effectors and that IL-2Rα expression by the APCs enhances memory formation, suggesting that transpresentation of IL-2 by APCs further amplifies IL-2 availability. Secondary memory generation was also avidity dependent. We propose that this regulatory pathway selects CD4 effectors of highest affinity to progress to memory.
MeSH term(s)	Mice ; Animals ; CD4-Positive T-Lymphocytes/metabolism ; Interleukin-2/metabolism ; Peptides/metabolism ; Mice, Transgenic ; Receptors, Antigen, T-Cell/metabolism ; Immunologic Memory ; Mice, Inbred C57BL
Chemical Substances	Interleukin-2 ; Peptides ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2023-10-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2200337
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Article ; Online: Durable CD4 T-Cell Memory Generation Depends on Persistence of High Levels of Infection at an Effector Checkpoint that Determines Multiple Fates.

Swain, Susan L / Jones, Michael C / Devarajan, Priyadharshini / Xia, Jingya / Dutton, Richard W / Strutt, Tara M / McKinstry, K Kai

Cold Spring Harbor perspectives in biology

2021 Volume 13, Issue 11

Abstract: We have discovered that the determination of CD4 effector and memory fates after infection is regulated not only by initial signals from antigen and pathogen recognition, but also by a second round of such signals at a checkpoint during the effector ... ...

Abstract	We have discovered that the determination of CD4 effector and memory fates after infection is regulated not only by initial signals from antigen and pathogen recognition, but also by a second round of such signals at a checkpoint during the effector response. Signals to effectors determine their subsequent fate, inducing further progression to tissue-restricted follicular helpers, cytotoxic CD4 effectors, and long-lived memory cells. The follicular helpers help the germinal center B-cell responses that give rise to high-affinity long-lived antibody responses and memory B cells that synergize with T-cell memory to provide robust long-lived protection. We postulate that inactivated vaccines do not provide extended signals from antigen and pathogen beyond a few days, and thus elicit ineffective CD4 T- and B-cell effector responses and memory. Defining the mechanisms that underlie effective responses should provide insights necessary to develop vaccine strategies that induce more effective and durable immunity.
MeSH term(s)	Animals ; Antigen Presentation ; CD4-Positive T-Lymphocytes/physiology ; Humans ; Immunologic Memory ; Infections/immunology ; Influenza Vaccines/immunology ; Pathogen-Associated Molecular Pattern Molecules
Chemical Substances	Influenza Vaccines ; Pathogen-Associated Molecular Pattern Molecules
Language	English
Publishing date	2021-11-01
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1943-0264
ISSN (online)	1943-0264
DOI	10.1101/cshperspect.a038182
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Article ; Online: Prostasin regulates PD-L1 expression in human lung cancer cells.

Chen, Li-Mei / Chai, Julius C / Liu, Bin / Strutt, Tara M / McKinstry, K Kai / Chai, Karl X

Bioscience reports

2021 Volume 41, Issue 7

Abstract: The serine protease prostasin is a negative regulator of lipopolysaccharide-induced inflammation and has a role in the regulation of cellular immunity. Prostasin expression in cancer cells inhibits migration and metastasis, and reduces epithelial- ... ...

Abstract	The serine protease prostasin is a negative regulator of lipopolysaccharide-induced inflammation and has a role in the regulation of cellular immunity. Prostasin expression in cancer cells inhibits migration and metastasis, and reduces epithelial-mesenchymal transition. Programmed death-ligand 1 (PD-L1) is a negative regulator of the immune response and its expression in cancer cells interferes with immune surveillance. The aim of the present study was to investigate if prostasin regulates PD-L1 expression. We established sublines overexpressing various forms of prostasin as well as a subline deficient for the prostasin gene from the Calu-3 human lung cancer cells. We report here that PD-L1 expression induced by interferon-γ (IFNγ) is further enhanced in cells overexpressing the wildtype membrane-anchored prostasin. The PD-L1 protein was localized on the cell surface and released into the culture medium in extracellular vesicles (EVs) with the protease-active prostasin. The epidermal growth factor-epidermal growth factor receptor (EGF-EGFR), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) participated in the prostasin-mediated up-regulation of PD-L1 expression. A Gene Set Enrichment Analysis (GSEA) of patient lung tumors in The Cancer Genome Atlas (TCGA) database revealed that prostasin and PD-L1 regulate common signaling pathways during tumorigenesis and tumor progression.
MeSH term(s)	Adenocarcinoma of Lung/enzymology ; Adenocarcinoma of Lung/genetics ; Adenocarcinoma of Lung/immunology ; B7-H1 Antigen/genetics ; B7-H1 Antigen/metabolism ; Cell Line, Tumor ; Epidermal Growth Factor/pharmacology ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Extracellular Vesicles/drug effects ; Extracellular Vesicles/enzymology ; Extracellular Vesicles/genetics ; Extracellular Vesicles/immunology ; Gene Expression Regulation, Neoplastic ; Humans ; Interferon-gamma/pharmacology ; Lung Neoplasms/enzymology ; Lung Neoplasms/genetics ; Lung Neoplasms/immunology ; Mitogen-Activated Protein Kinases/metabolism ; Protein Kinase C/metabolism ; Serine Endopeptidases/genetics ; Serine Endopeptidases/metabolism ; Signal Transduction ; Up-Regulation
Chemical Substances	B7-H1 Antigen ; CD274 protein, human ; Epidermal Growth Factor (62229-50-9) ; Interferon-gamma (82115-62-6) ; EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; Protein Kinase C (EC 2.7.11.13) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Serine Endopeptidases (EC 3.4.21.-) ; prostasin (EC 3.4.21.-)
Language	English
Publishing date	2021-07-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	764946-0
ISSN	1573-4935 ; 0144-8463
ISSN (online)	1573-4935
ISSN	0144-8463
DOI	10.1042/BSR20211370
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Article ; Online: Prostasin regulates PD-L1 expression in human lung cancer cells.

Chen, Li-Mei / Chai, Julius C / Liu, Bin / Strutt, Tara M / McKinstry, K Kai / Chai, Karl X

Bioscience reports

2021

Abstract	The serine protease prostasin is a negative regulator of lipopolysaccharide-induced inflammation and has a role in the regulation of cellular immunity. Prostasin expression in cancer cells inhibits migration and metastasis, and reduces epithelial-mesenchymal transition. Programmed death-ligand 1 (PD-L1) is a negative regulator of the immune response and its expression in cancer cells interferes with immune surveillance. The aim of this study was to investigate if prostasin regulates PD-L1 expression. We established sublines over-expressing various forms of prostasin as well as a subline deficient for the prostasin gene from the Calu-3 human lung cancer cells. We report here that PD-L1 expression induced by interferon-gamma (IFNg) is further enhanced in cells over-expressing the wild-type membrane-anchored prostasin. The PD-L1 protein was localized on the cell surface and released into the culture medium in extracellular vesicles (EVs) with the protease-active prostasin. The epidermal growth factor-epidermal growth factor receptor (EGF-EGFR), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) participated in the prostasin-mediated up-regulation of PD-L1 expression. A Gene Set Enrichment Analysis (GSEA) of patient lung tumors in The Cancer Genome Atlas (TCGA) database revealed that prostasin and PD-L1 regulate common signaling pathways during tumorigenesis and tumor progression.
Language	English
Publishing date	2021-06-28
Publishing country	England
Document type	Journal Article
ZDB-ID	764946-0
ISSN	1573-4935 ; 0144-8463
ISSN (online)	1573-4935
ISSN	0144-8463
DOI	10.1042/BCJ20210407
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Article ; Online: T-bet optimizes CD4 T-cell responses against influenza through CXCR3-dependent lung trafficking but not functional programming.

Dhume, Kunal / Finn, Caroline M / Strutt, Tara M / Sell, Stewart / McKinstry, K Kai

Mucosal immunology

2019 Volume 12, Issue 5, Page(s) 1220–1230

Abstract: Although clearance of many intracellular pathogens requires T-bet-dependent CD4 T cell programming, the extent to which T-bet is needed to direct protective CD4 responses against influenza is not known. Here, we characterize wild-type and T-bet-deficient ...

Abstract	Although clearance of many intracellular pathogens requires T-bet-dependent CD4 T cell programming, the extent to which T-bet is needed to direct protective CD4 responses against influenza is not known. Here, we characterize wild-type and T-bet-deficient CD4 cells during murine influenza infection. Surprisingly, although T-bet expression has broad impacts on cytokine production by virus-specific CD4 cells, the protective efficacy of T-bet-deficient effector cells is only marginally reduced. This reduction is due to lower CXCR3 expression, leading to suboptimal accumulation of activated T-bet-deficient cells in the infected lung. However, T-bet-deficient cells outcompete wild-type cells to form lung-resident and circulating memory populations following viral clearance, and primed T-bet-deficient mice efficiently clear supralethal heterosubtypic influenza challenges even when depleted of CD8 T cells. These results are relevant to the identification of more incisive correlates of protective T cells and for vaccines that aim to induce durable cellular immunity against influenza.
MeSH term(s)	Animals ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; Disease Resistance/genetics ; Disease Resistance/immunology ; Gene Expression ; Host-Pathogen Interactions/immunology ; Influenza A virus/immunology ; Lung/immunology ; Lung/metabolism ; Lung/pathology ; Mice ; Mice, Knockout ; Orthomyxoviridae Infections/immunology ; Orthomyxoviridae Infections/metabolism ; Orthomyxoviridae Infections/virology ; Receptors, CXCR3/metabolism ; Signal Transduction ; T-Box Domain Proteins/genetics ; T-Box Domain Proteins/metabolism ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; T-Lymphocytes, Helper-Inducer/immunology ; T-Lymphocytes, Helper-Inducer/metabolism
Chemical Substances	CXCR3 protein, human ; Cytokines ; Receptors, CXCR3 ; T-Box Domain Proteins ; T-box transcription factor TBX21
Language	English
Publishing date	2019-07-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2411370-0
ISSN	1935-3456 ; 1933-0219
ISSN (online)	1935-3456
ISSN	1933-0219
DOI	10.1038/s41385-019-0183-z
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Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito