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  • The American Association of Immunologists  (7)
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  • The American Association of Immunologists  (7)
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  • 1
    Online Resource
    Online Resource
    Med1 Controls Effector CD8+ T Cell Differentiation and Survival through C/EBPβ-Mediated Transcriptional Control of T-bet
    The American Association of Immunologists ; 2022
    In:  The Journal of Immunology Vol. 209, No. 5 ( 2022-09-01), p. 855-863
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 209, No. 5 ( 2022-09-01), p. 855-863
    Abstract: Effector CD8+ T cells are crucial players in adaptive immunity for effective protection against invading pathogens. The regulatory mechanisms underlying CD8+ T cell effector differentiation are incompletely understood. In this study, we defined a critical role of mediator complex subunit 1 (Med1) in controlling effector CD8+ T cell differentiation and survival during acute bacterial infection. Mice with Med1-deficient CD8+ T cells exhibited significantly impaired expansion with evidently reduced killer cell lectin-like receptor G1+ terminally differentiated and Ly6c+ effector cell populations. Moreover, Med1 deficiency led to enhanced cell apoptosis and expression of multiple inhibitory receptors (programmed cell death 1, T cell Ig and mucin domain–containing-3, and T cell immunoreceptor with Ig and ITIM domains). RNA-sequencing analysis revealed that T-bet– and Zeb2-mediated transcriptional programs were impaired in Med1-deficient CD8+ T cells. Overexpression of T-bet could rescue the differentiation and survival of Med1-deficient CD8+ effector T cells. Mechanistically, the transcription factor C/EBPβ promoted T-bet expression through interacting with Med1 in effector T cells. Collectively, our findings revealed a novel role of Med1 in regulating effector CD8+ T cell differentiation and survival in response to bacterial infection.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.2200037
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2022
    detail.hit.zdb_id: 1475085-5
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  • 2
    Online Resource
    Online Resource
    The Transcription Factor Zfp335 Promotes Differentiation and Persistence of Memory CD8+ T Cells by Regulating TCF-1
    The American Association of Immunologists ; 2022
    In:  The Journal of Immunology Vol. 209, No. 5 ( 2022-09-01), p. 886-895
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 209, No. 5 ( 2022-09-01), p. 886-895
    Abstract: Memory CD8+ T cells play an essential role in providing effective and lifelong protection against pathogens. Comprehensive transcriptional and epigenetic networks are involved in modulating memory T cell development, but the molecular regulations of CD8+ memory T cell formation and long-term persistence remain largely unknown. In this study, we show that zinc finger protein 335 (Zfp335) is indispensable for CD8+ T cell memory establishment and maintenance during acute infections. Mice with Zfp335 deletion in CD8+ T cells exhibit a significant reduction of memory T cells and memory precursor cells in the contraction phase. Zfp335 deficiency in CD8+ T cells resulted in decreased expression of memory featured genes Eomes and IL-2Rβ, leading to a loss of memory identity and an increase of apoptosis in response to IL-7 and IL-15. Mechanistically, Zfp335 directly binds to and regulates TCF-1, known to be critical for memory T cell development. Importantly, overexpression TCF-1 could rescue the defects in the survival of both CD8+ memory precursors and memory T cells caused by Zfp335 deficiency. Collectively, our findings reveal that Zfp335 serves as a novel transcriptional factor upstream of TCF-1 in regulating CD8+ T cell memory.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.2200026
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2022
    detail.hit.zdb_id: 1475085-5
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Phosphatase Wip1 Is Essential for the Maturation and Homeostasis of Medullary Thymic Epithelial Cells in Mice
    The American Association of Immunologists ; 2013
    In:  The Journal of Immunology Vol. 191, No. 6 ( 2013-09-15), p. 3210-3220
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 191, No. 6 ( 2013-09-15), p. 3210-3220
    Abstract: Thymic epithelial cells (TECs) are a key cell type in the thymic microenvironment essential for T cell development. However, intrinsic molecular mechanisms controlling TEC differentiation and activities are poorly defined. In this study, we found that deficiency of p53-induced phosphatase 1 (Wip1) in mice selectively caused severe medullary TEC (mTEC) maturation defects in an intrinsic manner. Wip1 knockout (KO) mice had decreased mature epithelial cell adhesion molecule+Ulex europaeus agglutinin-1 (UEA-1)+ mTECs, including UEA-1+MHC class IIhigh, UEA-1+CD80+, UEA-1+CD40+, and UEA-1+Aire+ cells, but not decreased numbers of cortical epithelial cell adhesion molecule+BP-1+ TECs, in the postnatal stage but not in the fetal stage. Wip1-deficient mTECs express fewer tissue-restricted Ags and UEA-1+involucrin+ terminal-differentiated cells. Animal models, including grafting fetal Wip1-deficient thymic tissue into T cell–deficient nude mice and reconstitution of lethally irradiated Wip1KO mouse recipients with wild-type bone marrow cells, also showed the impaired mTEC components in Wip1KO thymi, indicating the intrinsic regulatory role of Wip1 in mTEC maturation. Furthermore, thymus regeneration was significantly less efficient in adult Wip1KO mice than in wild-type mice after cyclophosphamide treatment. Wip1 deficiency resulted in elevated p38 MAPK activity in mTECs. Activated p38 MAPK has the ability to suppress CD40 expression on mTECs. Wip1-deficient thymi displayed poor response to CD40L in the fetal thymus organ culture system. Thus, Wip1 positively controls mTEC maturation, homeostasis, and regeneration through limiting the p38 MAPK pathway.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1300363
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2013
    detail.hit.zdb_id: 1475085-5
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    Online Resource
  • 4
    Online Resource
    Online Resource
    Cytometric analysis authenticates adjuvanticity of interferon-γ and suggests potential synergy with toll-like receptor agonists
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 145.03-145.03
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 145.03-145.03
    Abstract: Interferon-γ (IFN-γ) is a cytokine that plays an important role in immune regulation, especially in the activation and differentiation of immune cells. Toll-like receptors (TLRs) are a family of pattern-recognition receptors that sense structural motifs related to pathogens and alert immune cells to the invasion. Both IFN-γ and TLR agonists have been investigated as immunoadjuvants to augment the efficacy of cancer immunotherapies and vaccines against infectious diseases. In this study, we aimed to explore the potentiality of IFN-γ and TLR agonists being applied as dual adjuvant systems. In brief, murine dendritic cells were treated with IFN-γ and/or the TLR agonists, polyinosinic-polycytidylic acid (poly I:C) or resiquimod (R848). Subsequently, the cells were stained for an activation marker, cluster of differentiation 86 (CD86), and the percentage of CD86-positive cells was measured by flow cytometry. IFN-γ efficiently stimulated a considerable number of the dendritic cells, while the TLR agonists by themselves could merely activate a few compared to the control. The combination of IFN-γ with poly I:C or R848 triggered a higher amount of cell activation than IFN-γ alone. For instance, 10 ng/mL IFN-γ with 100 μg/mL poly I:C achieved 59.1% cell activation, which was significantly higher than the 33.4% positive cells obtained by 10 ng/mL IFN-γ (p= 0.0004). These results suggested that IFN-γ and TLR agonists could be applied as a complementary, dual adjuvant system to promote dendritic cell activation and antigen presentation. Additionally, there might be a synergy between the two classes of adjuvants, and further investigation is warranted to ascertain the interaction of their adjuvant activities. This work was supported by the NIDA/NIH award UG3DA048775.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.145.03
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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    Online Resource
  • 5
    Online Resource
    Online Resource
    Deciphering immunological mechanisms underlying the efficacy of nanoparticle-based vaccines against opioid use disorder (OUD)
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 71.20-71.20
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 71.20-71.20
    Abstract: The highly complex OUD and overdose epidemic poses a huge public health and economic burden, urging the need for safe and more effective therapeutic options. Vaccines offer a promising strategy for OUD treatment and prevention of overdose. Vaccinating against opioids generates drug-specific polyclonal antibodies (Ab) that selectively bind targeted opioids, blocking their distribution to the brain and thus blunting opioid induced rewards, pharmacological and side effects. Previous clinical trials of addiction vaccines showed proof of efficacy only in subjects with the highest Ab titers, highlighting the need to design more effective vaccines. The generation of a robust anti-drug polyclonal Abs response relies on CD4+ T cell-dependent B cell activation, hence dendritic cells (DC) are crucial for initiating CD4+ T cells priming and B cell responses. To improve vaccine formulation, we are exploiting a lipid-polymer hybrid nanoparticle (LPNP) platform and toll-like receptor (TLR) agonists to potentiate antigen recognition by antigen presenting cells (APCs) and subsequently the efficacy of anti-opioid conjugate vaccines. Using a flow cytometry-based in vitro activation assay, we demonstrated that LPNP-based vaccines are more effective in inducing macrophages activation marker (iNOS) and DCs co-stimulatory molecules and maturation markers (CD86, CD40, and MHC II) compared to conventional vaccines. Adding selected TLR agonists further improved nanovaccine efficacy in inducing the maturation and activation of APCs. These findings were confirmed with RT-qPCR quantifying mRNA expression of above-mentioned markers. These studies will identify key APCs subsets contributing to vaccine efficacy against OUD and other targets. Supported by grants from NIH (UG3/UH3 DA048775)
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.71.20
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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    Online Resource
  • 6
    Online Resource
    Online Resource
    In silico design of a universal carrier protein: A potential solution to the variable immunogenicity observed in past vaccines against drugs of abuse
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 169.2-169.2
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 169.2-169.2
    Abstract: Vaccines against drugs of abuse (VADAs) show promise as a possible therapeutic for the alleviation of addiction due to their ability to modulate intake behavior via the altering of drug pharmacokinetics. In the past, however, these vaccines have failed to show clinical efficacy due to extensive variability in the magnitude of antibody response between individual vaccinees. Correspondingly, the future success of VADAs hinges directly on whether or not researchers can find ways to engineer more broadly effective vaccines. Differences in response must, to some extent, be the result of variable capacities for each individual’s immune system to process and/or present antigens. As such, we speculate that future VADAs will need to target the three key stages of vaccine processing, recognition, processing, and presentation, in order to achieve clinical effectiveness. Here, we describe a project aiming to engineer a broadly effective carrier protein based on this concept. Using haplotype frequency data provided by Be the Match, HLA-DQ and -DR haplotypes covering 99% of the population were selected for analysis. Next, the most common carrier proteins used in conjugate vaccine formulations were analyzed for MHC II epitope content using these haplotypes and NetMHCIIPan 3.2 prediction software. Finally, a modified version of the prediction output was used to excise the most likely MHC II epitopes. The highest-ranked epitopes were then stitched together using linkers designed with chemical conjugation sites and cathepsin cleavage sequences and subsequently tethered to cholera toxin subunit B. These results present the successful design of an in silico derived, broadly effective carrier protein to be used in future VADA formulations.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.169.2
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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    Online Resource
  • 7
    Online Resource
    Online Resource
    In vitro validation of Cathepsin S docking models
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 221.25-221.25
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 221.25-221.25
    Abstract: In dendritic cells, the dominant lysosomal protease involved in Ii chain degradation and antigen digestion is Cathepsin S, a cysteine protease in the papain family. Extracellularly, Cathepsin S also contributes to pathological processes in cardiovascular disease, cancer, and autoimmune arthritis: unlike most lysosomal proteases, it retains its activity at serum pH. In computational molecular docking studies comparing peptides from the literature, we found that Cathepsin S shows a pH-dependent specificity switch, with predicted dissociation constants for specific peptide sequences differing at lysosomal and serum pH. The aim of this study is to further characterize this specificity switch and to compare docking results to kinetic parameters of Cathepsin S digestion in vitro. We identified peptide sequences of interest from docking, including sequences from the Ii chain and elastin, and digested these peptides (LifeTein) using human Cathepsin S (Calbiochem), collecting samples for LC-MS analysis over 16 hour reaction times. We report the kinetic parameters of Cathepsin S catalysis at both lysosomal and serum pH. Digestion results are compared to docking models and the models most predictive of catalytic activity are identified. Further investigation is needed to determine whether pH-dependent catalytic activity and selectivity of Cathepsin S will enable the design of protein-based therapies and inhibitors optimized for their targeted microenvironments. This work was partially supported by the NIDA/NIH award UG3DA048775, the USDA National Institute of Food and Agriculture, AFRI project #2021-0858, and the department of Biological Systems Engineering at Virginia Tech.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.221.25
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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    Online Resource
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