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  • The American Association of Immunologists  (8)
  • Medicine  (8)
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  • The American Association of Immunologists  (8)
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  • Medicine  (8)
RVK
  • 1
    Online Resource
    Online Resource
    Structural characterization of TLRs with novel agonists
    The American Association of Immunologists ; 2017
    In:  The Journal of Immunology Vol. 198, No. 1_Supplement ( 2017-05-01), p. 129.4-129.4
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 1_Supplement ( 2017-05-01), p. 129.4-129.4
    Abstract: Small molecule TLR4 and TLR2 agonists have been reported, but no structural data reveals their activation mechanism and detailed interactions with the TLRs. We have developed two small molecule agonists, Neoseptin-3 and Diprovocim, that activate TLR4/MD-2 and TLR1/TLR2 complexes, respectively, with exquisitely specific structure activity relationships. These two molecules bear no structural similarity to the natural ligands, lipopolysaccharide (LPS) and tri-acylated lipopeptide (Pam3CSK4). The crystal structures of Neoseptin-3 in complex with mouse TLR4/MD-2 and Diprovocim in complex with human TLR2 provide the first glimpse of how these TLRs bind to unconventional agonists, revealing unique and unexpected binding modes. Neoseptin-3 binds as an asymmetrical dimer within the hydrophobic pocket of MD-2, and induces an active receptor complex (a dimer of TLR4/MD-2) similar to that induced by lipid A. However, Neoseptin-3 and lipid A form different molecular contacts with TLR4/MD-2 to achieve receptor activation. Diprovocim forms a symmetrical dimer and interacts with the same hydrophobic pocket of TLR2 as Pam3CSK4, inducing homodimerization of TLR2 that has a different conformation than the active TLR1/TLR2 heterodimer. Diprovocim binds to TLR2 through an extensive intermolecular hydrogen bonding network that is not observed in the Pam3CSK4/TLR2/TLR1 structure. These two structures are now guiding us in optimization of TLR4/MD-2 and TLR1/TLR2 agonists and antagonists for clinical applications.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.198.Supp.129.4
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2017
    detail.hit.zdb_id: 1475085-5
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Identification of novel and potent synthetic TLR agonists
    The American Association of Immunologists ; 2017
    In:  The Journal of Immunology Vol. 198, No. 1_Supplement ( 2017-05-01), p. 129.3-129.3
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 1_Supplement ( 2017-05-01), p. 129.3-129.3
    Abstract: Agonists and antagonists of Toll-like receptors (TLRs) may be useful as vaccine adjuvants or suppressors of inflammation, respectively. In an effort to identify compounds capable of activating macrophages via TLRs or other sensors, a synthetic compound library was screened using mouse peritoneal macrophages and human THP-1 cells. Through extensive SAR studies of initial hits, we developed two strong synthetic agonists: Neoseptin-3 and Diprovocim. Genetic studies established that neoseptin-3 is a mouse TLR4/MD-2 agonist with no structural similarity to LPS. It activates mTLR4/MD-2 independently of CD14 and triggers canonical MyD88- and TRIF-dependent signaling. Diprovocim was found by a combination of genetic and antibody blockade analyses to be a TLR1/2 agonist, active on both mouse and human receptors. Its EC50 in human THP-1 cells is 110 pM. Diprovocim showed TLR1/2 dependent adjuvant activity when co-administered with ovalbumin (OVA). It not only promoted antigen-specific humoral responses but also activated cytotoxic T lymphocyte responses in a TLR1/2 dependent manner. Since neither Neoseptin-3 nor Diprovocim resemble the natural ligands for TLR4/MD-2 nor TLR1/2, respectively, we surmise that other “unconventional” ligands for these TLRs may exist in nature. However, the exquisite SAR of both compounds makes it clear that TLRs are not highly promiscuous receptors; on the contrary, they are activated only by compounds that fulfill strict structural rules. In finding these agonists, we also identified antagonists that bind the TLR complexes but do not activate them. The parent compounds Neoseptin-3 and Diprovocim will be used to develop new agonists and antagonists optimized for clinical application.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.198.Supp.129.3
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2017
    detail.hit.zdb_id: 1475085-5
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    Online Resource
  • 3
    Online Resource
    Online Resource
    The Natural Product Phyllanthusmin C Enhances IFN-γ Production by Human NK Cells through Upregulation of TLR-Mediated NF-κB Signaling
    The American Association of Immunologists ; 2014
    In:  The Journal of Immunology Vol. 193, No. 6 ( 2014-09-15), p. 2994-3002
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 193, No. 6 ( 2014-09-15), p. 2994-3002
    Abstract: Natural products are a major source for cancer drug development. NK cells are a critical component of innate immunity with the capacity to destroy cancer cells, cancer-initiating cells, and clear viral infections. However, few reports describe a natural product that stimulates NK cell IFN-γ production and unravel a mechanism of action. In this study, through screening, we found that a natural product, phyllanthusmin C (PL-C), alone enhanced IFN-γ production by human NK cells. PL-C also synergized with IL-12, even at the low cytokine concentration of 0.1 ng/ml, and stimulated IFN-γ production in both human CD56bright and CD56dim NK cell subsets. Mechanistically, TLR1 and/or TLR6 mediated PL-C’s activation of the NF-κB p65 subunit that in turn bound to the proximal promoter of IFNG and subsequently resulted in increased IFN-γ production in NK cells. However, IL-12 and IL-15Rs and their related STAT signaling pathways were not responsible for the enhanced IFN-γ secretion by PL-C. PL-C induced little or no T cell IFN-γ production or NK cell cytotoxicity. Collectively, we identify a natural product with the capacity to selectively enhance human NK cell IFN-γ production. Given the role of IFN-γ in immune surveillance, additional studies to understand the role of this natural product in prevention of cancer or infection in select populations are warranted.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1302600
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2014
    detail.hit.zdb_id: 1475085-5
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    Online Resource
  • 4
    Online Resource
    Online Resource
    Foxp1 Regulates Anti-tumor Effector Functions of CD8+ T cells in Ovarian Cancer (46.46)
    The American Association of Immunologists ; 2012
    In:  The Journal of Immunology Vol. 188, No. 1_Supplement ( 2012-05-01), p. 46.46-46.46
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 188, No. 1_Supplement ( 2012-05-01), p. 46.46-46.46
    Abstract: T cell based adoptive immunotherapy induces potent anti-tumor response in many cancers. Highly immunosuppressive tumor microenvironment, however, severely impairs effector functions and survival of transferred T cells. In order to gain the best possible immune elimination of tumor cells, specific molecular changes that impair T cell effector functions in the tumor microenvironment need to be identified and targeted. We recently reported that transcription factor Foxp1 critically regulates T cell effector functions as Foxp1-deficient CD8+T cells are better effectors. Here we demonstrate that immunosuppressive tumor microenvironment results in the upregulation of Foxp1 in tumor-reactive T cells, and impairs their effector functions. Consequently, mice bearing ovarian tumors survived significantly longer upon receiving adoptively transferred tumor-primed Foxp1-deficient T cells. In vitro studies further showed that Foxp1-deficient CD8+ T cells can proliferate better in the presence of immunosuppressive TGFb1. Analysis of adoptively transferred T cells showed that, compared to WT CD8+ T cells, Foxp1-deficient CD8+, but not CD4+, T cells survive better in the immunosuppressive tumor microenvironment. Tumor bearing mice receiving Foxp1-deficient effector T cells rejected secondary tumors indicating generation of anti-tumor T cell memory. Our findings indicate that targeting the transcription factor Foxp1 on effector T cells can dramatically improve anti-tumor immunotherapy.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.188.Supp.46.46
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2012
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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    Online Resource
  • 5
    Online Resource
    Online Resource
    Lis1 Regulates Germinal Center B Cell Antigen Acquisition and Affinity Maturation
    The American Association of Immunologists ; 2017
    In:  The Journal of Immunology Vol. 198, No. 11 ( 2017-06-01), p. 4304-4311
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 11 ( 2017-06-01), p. 4304-4311
    Abstract: The germinal center (GC) is the site where activated B cells undergo rapid expansions, somatic hypermutation, and affinity maturation. Affinity maturation is a process of Ag-driven selection. The amount of Ag acquired and displayed by GC B cells determines whether it can be positively selected, and therefore Ag acquisition has to be tightly regulated to ensure the efficient affinity maturation. Cell expansion provides sufficient quantity of GC B cells and Abs, whereas affinity maturation improves the quality of Abs. In this study, we found that Lis1 is a cell-intrinsic regulator of Ag acquisition capability of GC B cells. Lack of Lis1 resulted in redistribution of polymerized actin and accumulation of F-actin at uropod; larger amounts of Ags were acquired and displayed by GC B cells, which presumably reduced the selection stringency. Affinity maturation was thus compromised in Lis1-deficient mice. Consistently, overexpression of Lis1 in GC B cells led to less Ag acquisition and display. Additionally, Lis1 is required for GC B cell expansion, and Lis1 deficiency blocked the cell cycle at the mitotic phase and GC B cells were prone to apoptosis. Overall, we suggest that Lis1 is required for GC B cell expansion, affinity maturation, and maintaining functional intact GC response, thus ensuring both the quantity and quality of Ab response.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1700159
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2017
    detail.hit.zdb_id: 1475085-5
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    Online Resource
  • 6
    Online Resource
    Online Resource
    Quiescence regulator Foxp1 restrains antigen-induced T cell activation and response by mechanisms including a novel negative feedback loop (121.17)
    The American Association of Immunologists ; 2012
    In:  The Journal of Immunology Vol. 188, No. 1_Supplement ( 2012-05-01), p. 121.17-121.17
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 188, No. 1_Supplement ( 2012-05-01), p. 121.17-121.17
    Abstract: Previously we have shown that transcription factor Foxp1 is an essential regulator in maintaining the quiescence of naive T cells during homeostasis. In mice, Foxp1 has four isoforms. Now we find that whereas the full-length Foxp1A is constitutively expressed in mature T cells, T cell receptor (TCR) stimulation induces the expression of a short Foxp1 isoform, Foxp1D, which in turn dampens TCR signaling and T cell proliferation, constituting a negative feedback loop. In Foxp1D conditional transgenic mice, Foxp1D transgene in T cells reduces the generation of CD8+ and CD4+ T effectors to viral infections. On the contrary, Foxp1-deficient T cells (lacking all Foxp1 isoforms) elicit a faster and stronger effector response to antigen challenge. These results suggest that quiescence gene Foxp1 plays an important role in restraining antigen-induced T cell activation and response with a novel negative feedback loop by Foxp1D.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.188.Supp.121.17
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2012
    detail.hit.zdb_id: 1475085-5
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  • 7
    Online Resource
    Online Resource
    Leveraging CAR T cells to Achieve Desensitization and Enable Transplantation
    The American Association of Immunologists ; 2022
    In:  The Journal of Immunology Vol. 208, No. 1_Supplement ( 2022-05-01), p. 175.23-175.23
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 208, No. 1_Supplement ( 2022-05-01), p. 175.23-175.23
    Abstract: Pre-existing allo-antibodies (allo-Abs), that preclude transplant due to the risk of hyperacute rejection, lead to prolonged wait times and high mortality rates. Current desensitization approaches are ineffective as they do not adequately deplete allo-specific B cells and plasma cells (PCs). We hypothesize that stringent depletion of these cells is required to eliminate pre-existing allo-Abs. We leverage the exquisite ability of CAR T cells to eliminate target cells to desensitize transplant candidates. We constructed CARs targeting murine CD19 or BCMA, which cover the entire B cell-PC continuum. We first evaluated the function of CAR T cells against B cells and PCs in vitro. C57BL/6 mice were sensitized with BALB/c skin grafts. After skin rejection, sensitized mice received total body irradiation followed by treatment with either control T cells, CART-19 T cells, or a combination of CART-19 and CART-BCMA T cells (combo-CART). Allo-Abs, total Ig, and B cells were measured over 13 weeks. Functional desensitization was then assessed by induction of diabetes followed by BALB/c-derived islet cell transplant and glucose were measured to assess graft survival. CD19- and BCMA-targeted CARs effectively depleted primary B cells and PCs in vitro and in vivo. Control and CART-19 T cells were ineffective at desensitizing mice, but combo-CART treatment resulted in significant decrease of allo-Abs. Islet cell grafts succumbed to hyperacute rejection in 80% of control and CART-19 treated mice. However, combo-CART treatment resulted in prolonged graft survival in all mice (mean 35 days, range 16–60). Thus, CAR T cells targeting B cell and PC antigens represent a promising approach to desensitization and could enable lifesaving transplantation.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.208.Supp.175.23
    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
  • 8
    Online Resource
    Online Resource
    Integrin-Mediated Interactions between B Cells and Follicular Dendritic Cells Influence Germinal Center B Cell Fitness
    The American Association of Immunologists ; 2014
    In:  The Journal of Immunology Vol. 192, No. 10 ( 2014-05-15), p. 4601-4609
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 192, No. 10 ( 2014-05-15), p. 4601-4609
    Abstract: Integrin–ligand interactions between germinal center (GC) B cells and Ag-presenting follicular dendritic cells (FDCs) have been suggested to play central roles during GC responses, but their in vivo requirement has not been directly tested. In this study, we show that, whereas integrins αLβ2 and α4β1 are highly expressed and functional on mouse GC B cells, removal of single integrins or their ligands had little effect on B cell participation in the GC response. Combined β2 integrin deficiency and α4 integrin blockade also did not affect the GC response against a particulate Ag. However, the combined integrin deficiency did cause B cells to be outcompeted in splenic GC responses against a soluble protein Ag and in mesenteric lymph node GC responses against gut-derived Ags. Similar findings were made for β2-deficient B cells in mice lacking VCAM1 on FDCs. The reduced fitness of the GC B cells did not appear to be due to decreased Ag acquisition, proliferation rates, or pAKT levels. In summary, our findings provide evidence that αLβ2 and α4β1 play overlapping and context-dependent roles in supporting interactions with FDCs that can augment the fitness of responding GC B cells. We also find that mouse GC B cells upregulate αvβ3 and adhere to vitronectin and milk-fat globule epidermal growth factor VIII protein. Integrin β3-deficient B cells contributed in a slightly exaggerated manner to GC responses, suggesting this integrin has a regulatory function in GC B cells.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1400090
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2014
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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