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  • 1
    Online Resource
    Online Resource
    YAP is a novel regulator of CD4+ and CD8+ T cells during activation, differentiation, and anti-tumor immunity
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 72.14-72.14
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 72.14-72.14
    Abstract: Advanced understanding of T cell regulation has fueled cancer immunotherapy, but durable responses remain confined to a minority of patients. Poor responses can be linked to either suppressed T cell function in tumors or “cold” tumors that exclude immune cells. Identifying novel T cell regulators involved in these processes is a high priority. Our studies identified the protein YAP as a novel regulator of T cells. YAP mRNA and protein were rapidly expressed after T cell activation in mouse CD4+ and CD8+ T cells. T cell-specific Yap knockout (YapKO) generated CD4+ and CD8+ T cells that express elevated levels of activation markers (CD25, CD44, CD69) compared to WT cells. YapKO increased the sensitivity of T cells to anti-CD3 dose, and increased CD4+ T cell differentiation efficiency under Th1, Th2, Th17, and Treg skewing conditions. YapKO CD8+ T cells expanded & gt;20-fold more than WT when cultured in engineered hydrogel matrices optimized for T cell expansions and adoptive transfer. Syngeneic tumors grown in T cell YapKO mice had impaired growth and increased immune infiltration compared to tumors in WT hosts. Co-adoptive transfer of YapKO and WT CD8+ T cells showed only YapKO cells infiltrated B16F10 tumors. RNAseq of CD4+ and CD8+ T cells from tumors and draining lymph nodes showed gene expression changes including upregulation of T cell receptor and cytokine signaling pathways in YapKO hosts. T cells from tumor-draining lymph nodes were not significantly different between YapKO and WT. YapKO gene signatures correlated with immune infiltration and survival in multiple human cancers in TCGA. Our data demonstrated YAP is a novel regulator of diverse T cell functions and may be a useful target for enhancing responses to cancer immunotherapy.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.72.14
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
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  • 2
    Online Resource
    Online Resource
    MHC-based diagnostics and therapeutics – clinical applications for disease-linked genes
    Elsevier BV ; 1999
    In:  Immunology Today Vol. 20, No. 4 ( 1999-4), p. 161-165
    Details
    In: Immunology Today, Elsevier BV, Vol. 20, No. 4 ( 1999-4), p. 161-165
    Type of Medium: Online Resource
    ISSN: 0167-5699
    URL: Article
    DOI: 10.1016/S0167-5699(98)01390-5
    RVK:
    XA 10000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 1999
    detail.hit.zdb_id: 2013676-6
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Decline of influenza-specific CD8+ T cell repertoire in healthy geriatric donors
    Springer Science and Business Media LLC ; 2011
    In:  Immunity & Ageing Vol. 8, No. 1 ( 2011-12)
    Details
    In: Immunity & Ageing, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2011-12)
    Abstract: While influenza vaccination results in protective antibodies against primary infections, clearance of infection is primarily mediated through CD8 + T cells. Studying the CD8 + T cell response to influenza epitopes is crucial in understanding the disease associated morbidity and mortality especially in at risk populations such as the elderly. We compared the CD8 + T cell response to immunodominant and subdominant influenza epitopes in HLA-A2 + control, adult donors, aged 21-42, and in geriatric donors, aged 65 and older. Results We used a novel artificial Antigen Presenting Cell (aAPC) based stimulation assay to reveal responses that could not be detected by enzyme-linked immunosorbent spot (ELISpot). 14 younger control donors and 12 geriatric donors were enrolled in this study. The mean number of influenza-specific subdominant epitopes per control donor detected by ELISpot was only 1.4 while the mean detected by aAPC assay was 3.3 (p = 0.0096). Using the aAPC assay, 92% of the control donors responded to at least one subdominant epitopes, while 71% of control donors responded to more than one subdominant influenza-specific response. 66% of geriatric donors lacked a subdominant influenza-specific response and 33% of geriatric donors responded to only 1 subdominant epitope. The difference in subdominant response between age groups is statistically significant (p = 0.0003). Conclusion Geriatric donors lacked the broad, multi-specific response to subdominant epitopes seen in the control donors. Thus, we conclude that aging leads to a decrease in the subdominant influenza-specific CTL responses which may contribute to the increased morbidity and mortality in older individuals.
    Type of Medium: Online Resource
    ISSN: 1742-4933
    URL: Article
    DOI: 10.1186/1742-4933-8-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2011
    detail.hit.zdb_id: 2168941-6
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  • 4
    Online Resource
    Online Resource
    Probing T cell membrane organization using dimeric MHC–Ig complexes
    Elsevier BV ; 2002
    In:  Journal of Immunological Methods Vol. 268, No. 1 ( 2002-10), p. 93-106
    Details
    In: Journal of Immunological Methods, Elsevier BV, Vol. 268, No. 1 ( 2002-10), p. 93-106
    Type of Medium: Online Resource
    ISSN: 0022-1759
    URL: Article
    DOI: 10.1016/S0022-1759(02)00203-X
    RVK:
    XA 10000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2002
    detail.hit.zdb_id: 1500495-8
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  • 5
    Online Resource
    Online Resource
    Enhanced Antigen-Specific Antitumor Immunity with Altered Peptide Ligands that Stabilize the MHC-Peptide-TCR Complex
    Elsevier BV ; 2000
    In:  Immunity Vol. 13, No. 4 ( 2000-10), p. 529-538
    Details
    In: Immunity, Elsevier BV, Vol. 13, No. 4 ( 2000-10), p. 529-538
    Type of Medium: Online Resource
    ISSN: 1074-7613
    URL: Article
    DOI: 10.1016/S1074-7613(00)00052-2
    RVK:
    XA 48754.8
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2000
    detail.hit.zdb_id: 2001966-X
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  • 6
    Online Resource
    Online Resource
    Ex vivo induction and expansion of Natural Killer T cells by CD1d1-Ig coated artificial antigen presenting cells (41.22)
    The American Association of Immunologists ; 2009
    In:  The Journal of Immunology Vol. 182, No. 1_Supplement ( 2009-04-01), p. 41.22-41.22
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 182, No. 1_Supplement ( 2009-04-01), p. 41.22-41.22
    Abstract: Natural killer T (NKT) cells play a pivotal role in maintaining immune homeostasis. Many studies examining patients with cancer have shown that there is a reduction in both NKT cell number and function. Due to the complexities of manipulating NKT cells in vivo, ex vivo expanded effector NKT cells would be an excellent therapeutic modality. To date, immunotherapy utilizing the NKT/CD1d system has been dependent on the use of autologous antigen presenting cells pulsed with α-galactocylceramide (α-GalCer). In this study, we have generated CD1d- expressing artificial antigen presenting cells (aAPC) to examine co-stimulatory requirements for NKT cells and to expand NKT cells from the peripheral blood of healthy controls and cancer patients. We tracked the level of NKT cell expansion and the expanded population was characterized both phenotypically and functionally. We found that CD1d-based aAPC can effectively propagate both canonical (iNKT cells) and noncanonical NKT cells. Thus, CD1d-expressing aAPC will enhance our knowledge of NKT cell biology and could potentially be used as a novel tool in adoptive immunotherapeutic strategies.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.182.Supp.41.22
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2009
    detail.hit.zdb_id: 1475085-5
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  • 7
    Online Resource
    Online Resource
    In Vitro Expansion of Antigen-Specific CD8+ T Cells from Human PBMCs Using Artificial T-cell Stimulating Microparticles
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 145.02-145.02
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 145.02-145.02
    Abstract: While current T cell-based immunotherapies have shown moderate success, clinical translation of these methods has been hindered by biological variability, limited efficacy, and high expense. Here, we create a novel T cell stimulating platform for antigen-specific CD8+ T cell activation and expansion, eliminating the extensive ex vivoexpansion steps and thus making it accessible for many more cancer patients. The scaffold is formed using thiol-modified hyaluronic acid cross-linked with PEGDA, magnetic dextran nanoparticles, as well as DTT-reduced MHC-Ig dimer HLA-A*02 (A2) and anti-CD28. The gel is passed through a mesh device to form microparticles (MPs), which are then passively loaded with peptides (here, CMV and MART1) for ease of multiple expansions. They were plated with human PBMCs thawed overnight in culture media supplemented with human AB serum and a cocktail of cytokines (IL-1b, IL-2, IL-4, IL-6, and IFNγ). On days 7 and 14, cells were harvested and analyzed for proliferation of antigen-specific cells. After fourteen days of culturing PBMCs with A2 MPs, we could detect a significant expansion of antigen-specific T cells via flow cytometry. When stimulated with peptide-pulsed target cells for an intracellular cytokine assay, they expressed one or more of IFNγ, TNFα, and IL-2, demonstrating their polyfunctionality. We also observed a greater population of memory T cells, which indicates that these cells may persist longer in the body. We have developed a biomaterial-based T cell activation platform that provides critical signals, mimicking the lymph nodes. These MPs are effective in expanding antigen-specific T cells from human PBMCs, and these cells have robust killing of target splenocytes.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.145.02
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
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  • 8
    Online Resource
    Online Resource
    Harnessing the Fas pathway for type 1 diabetes therapy (128.29)
    The American Association of Immunologists ; 2007
    In:  The Journal of Immunology Vol. 178, No. 1_Supplement ( 2007-04-01), p. S216-S216
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 178, No. 1_Supplement ( 2007-04-01), p. S216-S216
    Abstract: The Fas pathway is not required for T cell activation yet loss-of-function mutation that inactivates Fas (lpr) or FasL (gld) prevents autoimmune diabetes in NOD mice without interfering with normal immune responses. However, the Fas pathway has not been considered a viable therapeutic option because these mutations also cause double negative (DN) T cell lymphoproliferation and lupus-like syndrome. Using bone marrow chimeras and adoptive transfer, we show that gld mutation on either hemopoietic or nonhemopoietic compartment is equally protective from autoimmune diabetes; however, gld mutation on hemopoietic cells is responsible for most of DN T cell lymphoproliferation. Therefore, limiting gld mutation to the nonhemopoietic tissue completely controls diabetogenicity of wild type T cells without causing lymphoproliferation. The protection is recapitulated therapeutically by treating NOD-wt mice with FasL neutralizing antibody. Anti-FasL treatment curtailed insulitis and did not lead to lupus-like disease or DN T cell lymphoproliferation. These results suggest the potential of generating a new class of immunotherapy that is based on targeting T cell apoptosis inducing ligand rather than costimulatory pathways.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.178.Supp.128.29
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2007
    detail.hit.zdb_id: 1475085-5
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  • 9
    Online Resource
    Online Resource
    Using nanoparticles as artificial antigen presenting cells to mobilize CD4 T cells for immunotherapy.
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 250.12-250.12
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 250.12-250.12
    Abstract: CD4 T cell-based adoptive cell transfer (ACT) therapies have clinical success across multiple cancer types, including metastatic melanoma and epithelial cancer. One of the challenges of ACT therapy is finding methods to expand tumor antigen-specific T cells ex vivo. Therefore, engineering platforms for antigen-specific T cell expansion are critical since they provide greater control over studying T cell biology and have significant translational relevance. We developed a nanoscale platform that expands murine and human antigen-specific T cells in vitro. This artificial antigen-presenting cells (aAPCs) platform provides T cells with two critical signals, MHC class II and anti-CD28, for T cell activation, which permits the activation of cognate antigen-specific CD4 T cells ex vivo. We isolate human CD4 T cells from PBMCs of healthy donors who are HLA DP4 +. We then stimulate CD4 T cells with aAPCs in media with inflammatory cytokine and access the specificity and effector function through tetramer staining, cytokine release assays, and killing assays. Co-culturing aAPCs and human CD4 T cells significantly increase the frequency of cognate antigen-specific CD4 T cells. Specifically, we expanded tetanus toxin-specific HLA-DP4 +CD4 T cells from healthy human PBMCs with aAPC. By the end of the expansion, the antigen-specific expanded from less than 1% to over 40% by day 21. In addition, the resulting antigen-specific cells display high levels of effector cytokine production, including TNF-a, IFN-g, IL-2, and granzyme B. Consistently, aAPC-activated CD4 T cells demonstrate robust lytic capacity in vitroand in vivo. These data show that aAPC can expand antigen-specific human cytotoxic CD4 T cells from a rare precursor population.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.250.12
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
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  • 10
    Online Resource
    Online Resource
    Tumor Associated Ascites Inhibits CD1d-Mediated NKT cell Activation (88.18)
    The American Association of Immunologists ; 2009
    In:  The Journal of Immunology Vol. 182, No. 1_Supplement ( 2009-04-01), p. 88.18-88.18
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 182, No. 1_Supplement ( 2009-04-01), p. 88.18-88.18
    Abstract: Natural killer T (NKT) cells recognize lipid antigen presented by CD1d molecules. It has been shown that NKT cells can both directly and indirectly mediate anti-tumor immunity. However, it is thought that the anti-tumor effects mediated by these cells are being hampered because the number and function of NKT cells are reduced in cancer patients. In addition, it has been shown that tumor associated glycolipids are frequently shed into the tumor microenvironment, which can mediate immunosuppressive activity. In these studies we examined antigen presentation by CD1d following treatment with ascites from ovarian cancer patients. It was found that pretreatment with ascites inhibited the ability of CD1d expressing cells to activate NKT cells in a dose-dependent manner. We found that this inhibition does not require antigen processing, as canonical (Vα14+) and noncanonical NKT cells, which do not require trafficking through endocytic compartments, were both inhibited. Also, ascites treatment of artificial Antigen Presenting Cells (aAPC) preloaded with α-GalCer, abrogated their ability to present antigen to NKT cells, which further suggests that the inhibition is antigen processing independent. In addition, our data demonstrate that treatment antigen presenting cells with ascites does not inhibit activation of classical CD8+ T cells. Together, these data suggest that glycolipid shedding in ascites may be a mechanism of immune evasion specifically utilized used by cancers to inhibit CD1d- mediated activation of NKT cells.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.182.Supp.88.18
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2009
    detail.hit.zdb_id: 1475085-5
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