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  • 1
    Online Resource
    Online Resource
    EspH Suppresses Erk by Spatial Segregation from CD81 Tetraspanin Microdomains
    American Society for Microbiology ; 2018
    In:  Infection and Immunity Vol. 86, No. 10 ( 2018-10)
    Details
    In: Infection and Immunity, American Society for Microbiology, Vol. 86, No. 10 ( 2018-10)
    Abstract: Enteropathogenic Escherichia coli (EPEC) belongs to a group of enteric human pathogens known as attaching-and-effacing (A/E) pathogens, which utilize a type III secretion system (T3SS) to translocate a battery of effector proteins from their own cytoplasm into host intestinal epithelial cells. Here we identified EspH to be an effector that prompts the recruitment of the tetraspanin CD81 to infection sites. EspH was also shown to be an effector that suppresses the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) signaling pathway at longer infection times. The inhibitory effect was abrogated upon deletion of the last 38 amino acids located at the C terminus of the protein. The efficacy of EspH-dependent Erk suppression was higher in CD81-deficient cells, suggesting that CD81 may act as a positive regulator of Erk, counteracting Erk suppression by EspH. EspH was found within CD81 microdomains soon after infection but was largely excluded from these domains at a later time. Based on our results, we propose a mechanism whereby CD81 is initially recruited to infection sites in response to EspH translocation. At a later stage, EspH moves out of the CD81 clusters to facilitate effective Erk inhibition. Moreover, EspH selectively inhibits the tumor necrosis factor alpha (TNF-α)-induced Erk signaling pathway. Since Erk and TNF-α have been implicated in innate immunity and cell survival, our studies suggest a novel mechanism by which EPEC suppresses these processes to promote its own colonization and survival in the infected gut.
    Type of Medium: Online Resource
    ISSN: 0019-9567 , 1098-5522
    URL: Article
    DOI: 10.1128/IAI.00303-18
    RVK:
    XA 10000
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2018
    detail.hit.zdb_id: 1483247-1
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  • 2
    Online Resource
    Online Resource
    Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis
    Springer Science and Business Media LLC ; 2021
    In:  Nature Vol. 597, No. 7877 ( 2021-09-23), p. 549-554
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 597, No. 7877 ( 2021-09-23), p. 549-554
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-021-03879-4
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 3
    Online Resource
    Online Resource
    The Tetraspanin CD81 Facilitates Tumor Metastasis By Modulating Immune Suppression
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 4136-4136
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 4136-4136
    Abstract: Tumor metastasis is the major cause of cancer mortality. While immune cells are aimed at halting metastases, the proliferating cancer cells at the primary tumor site recruit cells that counteract the adaptive anti-tumor immune response. Indeed, it is well established that tumors induce the accumulation and proliferation of immune suppressive cells, such as regulatory T cells (Tregs) and Myeloid Derived Suppressor cells (MDSC). The tetraspanin CD81 belongs to a family of proteins that play an important role in the immune system as evident by impaired immune functions of DCs, B and T cells in several tetraspanin-deficient mice (CD37, CD81, CD151, and CD82). While many studies have addressed the function of CD81 in infection and in the immune system, few have focused on its role in tumorigenesis and metastasis. Here we report that the growth of subcutaneously implanted breast cancer tumors (4T1) is slightly impaired in CD81 knockout (CD81KO) compared to wild type mice. Moreover, CD81KO mice develop very few lung metastases compared to their wild type and heterozygous counterparts. Both wild type and CD81KO tumor-bearing mice show substantial increases in Tregs, and MDSCs. However, these Tregs and MDSCs differ functionally - those derived from wild type mice are effective suppressors of T cell proliferation. By contrast, Tregs and MDSCs derived from tumor-bearing CD81KO mice do not suppress the proliferation of Teff cells. Thus, it is highly likely that while Teff cells are greatly restrained by Tregs and MDSCs in wild type tumor-bearing mice, the impairment of both suppressive cell populations in CD81KO mice enables the anti-tumor function thereby opposing metastases. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.4136.4136
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    Online Resource
    Online Resource
    CD81 association with SAMHD1 enhances HIV-1 reverse transcription by increasing dNTP levels
    Springer Science and Business Media LLC ; 2017
    In:  Nature Microbiology Vol. 2, No. 11 ( 2017-09-04), p. 1513-1522
    Details
    In: Nature Microbiology, Springer Science and Business Media LLC, Vol. 2, No. 11 ( 2017-09-04), p. 1513-1522
    Type of Medium: Online Resource
    ISSN: 2058-5276
    URL: Article
    DOI: 10.1038/s41564-017-0019-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2845610-5
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  • 5
    Online Resource
    Online Resource
    L111 and E605: vital residues in the functionality of the Bruton’s tyrosine kinase (153.18)
    The American Association of Immunologists ; 2011
    In:  The Journal of Immunology Vol. 186, No. 1_Supplement ( 2011-04-01), p. 153.18-153.18
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 186, No. 1_Supplement ( 2011-04-01), p. 153.18-153.18
    Abstract: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency due to mutations in the gene encoding Bruton’s tyrosine kinase (Btk). Btk is a key protein in the B cell receptor signaling pathway. Functional characterization of the mutated Btk in patients with XLA is important in order to define that they are disease causing mutations. Previously, we identified two novel missense mutations in Btk in XLA patients. Using in silico assays we determined that L111P and E605G produced modifications in the structural conformation, affecting the protein organization and its functionality. The absence of catalytic activity of Btk from the patients was reflected on the lack of the Y223 phosphorylation, lack of calcium release and aberrant Btk redistribution after BCR crosslinking. This work shows for that the L111 and E605 residues are fundamental for the activation and functionality of the Bruton’s tyrosine kinase. Additionaly, in silico analysis can be a useful tool for understanding Btk mutations found in primary immunodeficiency patients.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.186.Supp.153.18
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2011
    detail.hit.zdb_id: 1475085-5
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  • 6
    Online Resource
    Online Resource
    Construction and characterization of three chimeric proteins of CD38 (90.29)
    The American Association of Immunologists ; 2009
    In:  The Journal of Immunology Vol. 182, No. 1_Supplement ( 2009-04-01), p. 90.29-90.29
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 182, No. 1_Supplement ( 2009-04-01), p. 90.29-90.29
    Abstract: CD38 is a surface receptor as well as an enzyme present in various cell types, including B and T lymphocytes. It has been implicated in several biological functions such as chemotaxis, cell activation and proliferation, rescue or induction of apoptosis. It is not known how this molecule has different functions in different cells. CD31 was identified and characterized as a possible ligand; however, these data are still controversial. In the mouse there is less information, since only two molecules have been identified (without a definitive characterization) as potential ligands. In order to identify CD38 ligand(s) in mice, we designed three soluble chimeric proteins of CD38. One fused with CD8α, a second one fused with the Fc from the IgG1 immunoglobulin, both from human, and a third one containing only a V5 paramyxovirus epitope and a histidine tag. The proteins were characterized by Western blot and enzymatic activity assays. The results showed that all the proteins formed soluble dimers and exhibited enzymatic activity. With these tools, we obtained data suggesting the existence of a possible ligand present on the surface of CD11c+ cells from mice′s spleen. In conclusion the chimeric proteins can be useful tools to continue the characterization of potential ligands of CD38. Supported by CONACyT 56836.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.182.Supp.90.29
    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
    CD81 as a tumor target
    Portland Press Ltd. ; 2017
    In:  Biochemical Society Transactions Vol. 45, No. 2 ( 2017-04-15), p. 531-535
    Details
    In: Biochemical Society Transactions, Portland Press Ltd., Vol. 45, No. 2 ( 2017-04-15), p. 531-535
    Abstract: CD81 participates in a variety of important cellular processes such as membrane organization, protein trafficking, cellular fusion and cell–cell interactions. In the immune system, CD81 regulates immune synapse, receptor clustering and signaling; it also mediates adaptive and innate immune suppression. CD81 is a gateway in hepatocytes for pathogens such as hepatitis C virus and Plasmodium; it also confers susceptibility to Listeria infection. These diverse biological roles are due to the tendency of CD81 to associate with other tetraspanins and with cell-specific partner proteins, which provide the cells with a signaling platform. CD81 has also been shown to regulate cell migration and invasion, and has therefore been implicated in cancer progression. Indeed, we have recently shown that CD81 contributes to tumor growth and metastasis. CD81 is expressed in most types of cancer, including breast, lung, prostate, melanoma, brain cancer and lymphoma, and the overexpression or down-regulation of this molecule has been correlated with either good or bad prognosis. Here, we discuss the role of CD81 in cancer and its potential therapeutic use as a tumor target.
    Type of Medium: Online Resource
    ISSN: 0300-5127 , 1470-8752
    URL: Article
    DOI: 10.1042/BST20160478
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2017
    SSG: 12
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  • 8
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    Online Resource
    Macrophage Polarization by Tumor-induced MDSCs Assay
    Bio-Protocol, LLC ; 2016
    In:  BIO-PROTOCOL Vol. 6, No. 16 ( 2016)
    Details
    In: BIO-PROTOCOL, Bio-Protocol, LLC, Vol. 6, No. 16 ( 2016)
    Type of Medium: Online Resource
    ISSN: 2331-8325
    URL: Article
    DOI: 10.21769/BioProtoc.1900
    Language: English
    Publisher: Bio-Protocol, LLC
    Publication Date: 2016
    detail.hit.zdb_id: 2833269-6
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  • 9
    Online Resource
    Online Resource
    Treating B Cell Lymphomas with Anti CD81 Antibodies
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 4180-4180
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4180-4180
    Abstract: The tetraspanin CD81 associates with CD19 on B cells; this molecular complex functions as co-receptor to lower the threshold of BCR-initiated B cell activation. Recently we have shown the importance of CD81 in tumor growth and metastasis of solid tumors (Vences-Catalan et al., 2015). However, the role of CD81 in lymphoid malignancies has not been explored. Previous studies demonstrated anti-proliferative effects of anti-CD81 antibodies on human B cell lymphomas using in vitro assays (Oren et al., 1990). Here we tested the therapeutic effect of an anti-human CD81 antibody in vivo against Raji and SUP-B8 B cell lymphomas using a xenograft model in SCID mice. Our studies demonstrated that our anti-human CD81 antibody (mouse IgG1) had therapeutic effect comparable to Rituximab (human IgG1) (Figure 1A). Yet, the two antibodies differ in their ability to mediate antibody-dependent cell cytotoxicity (ADCC), Rituximab is known to be highly effective, whereas the mouse IgG1 anti-CD81 antibody is not expected to mediate ADCC. To enhance the anti-CD81-mediated ADCC, we class switched the hybridoma to mouse IgG2a; we also engineered a chimeric antibody containing human IgG1ADCC-HIGH Fc constant region. Indeed, mouse IgG2a and the chimeric human IgG1 anti-CD81 mAb showed a remarkable increase in NK cell-mediated ADCC as well as complement-dependent cytotoxicity (CDC) when compared to Rituximab in vitro (data not shown) and in vivo (Figure 1B). These results suggest that CD81 can be a potential therapeutic target on B cell lymphomas by virtue of both its direct cytotoxic effect and as a mediator of ADCC and CDC. The humanized IgG1 version is being developed as a therapeutic candidate. Comparable efficacy of anti-CD81 to Rituximab. SCID mice were I.V.-injected with 1.5x106 Raji-GFP-Luc cells, tumors growth proceeded for 5 days before IP injection of 4 weekly doses of 100 ug of the indicated antibodies. (A) Survival of Raji-GFP-Luc bearing SCID mice given anti CD81 (n=30), Rituximab (n=20) or control MsIgG1 (n=30). (B) In vivo bioluminescence imaging of tumor growth in mice injected (left to right) with control mouse IgG1; anti-CD81 (MsIgG1); anti-CD81 MsIgG2a; chimeric anti-CD81 (HuIgG1) and Rituximab. Comparable efficacy of anti-CD81 to Rituximab. SCID mice were I.V.-injected with 1.5x106 Raji-GFP-Luc cells, tumors growth proceeded for 5 days before IP injection of 4 weekly doses of 100 ug of the indicated antibodies. (A) Survival of Raji-GFP-Luc bearing SCID mice given anti CD81 (n=30), Rituximab (n=20) or control MsIgG1 (n=30). / (B) In vivo bioluminescence imaging of tumor growth in mice injected (left to right) with control mouse IgG1; anti-CD81 (MsIgG1); anti-CD81 MsIgG2a; chimeric anti-CD81 (HuIgG1) and Rituximab. Disclosures Levy: Kite Pharma: Consultancy; Five Prime Therapeutics: Consultancy; Innate Pharma: Consultancy; Beigene: Consultancy; Corvus: Consultancy; Dynavax: Research Funding; Pharmacyclics: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.4180.4180
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
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    Online Resource
    Abstract B061: CD81: A new target for therapy of B cell lymphoma
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Immunology Research Vol. 4, No. 11_Supplement ( 2016-11-01), p. B061-B061
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 4, No. 11_Supplement ( 2016-11-01), p. B061-B061
    Abstract: CD81 belongs to an evolutionary conserved family of proteins named tetraspanins and it was originally described as a B cell target. Tetraspanins associate in multi-molecular complexes in tetraspanin-enriched microdomains (TEMS). Indeed, in B cells CD81 associates with CD19 and CD21, and together function as co-receptor to lower the cell activation threshold initiated by the BCR. Recently, we have demonstrated the importance of CD81 in tumor growth and metastasis of solid tumors1. However, the role of CD81 in B cell malignancies has not been explored. Previously, we have shown that anti-CD81 antibodies had anti-proliferative effects on human B cell lymphoma cell lines in vitro2. Here we tested the therapeutic effect of a mouse anti-human CD81 antibody in vivo against Raji and SUP-B8 B cell lymphomas using a xenograft model in SCID mice. Our studies demonstrated that our anti-CD81 antibody had therapeutic effect comparable to rituximab. Moreover, we found ADCC as one of the mechanism of action. Furthermore, to enhance the anti-CD81-mediated ADCC we engineered chimeric antibodies containing human IgG1ADCC-HIGH and human IgG4 ADCC-LOW Fc constant regions. Indeed, the chimeric human IgG1 anti-CD81 mAb showed a remarkable increase in NK cell-mediated ADCC compared to Rituximab in vitro. These results suggest that CD81 can be a potential therapeutic target on B cell lymphomas by virtue of both its direct cytotoxic effect and as a mediator of ADCC. The Human IgG1 version is being developed as a therapeutic candidate. 1. Vences-Catalan, F., et al. Cancer Res 75, 4517-4526 (2015). 2. Oren, R., Takahashi, S., Doss, C., Levy, R. & Levy, S. Mol Cell Biol 10, 4007-4015 (1990). Citation Format: Felipe Vences-Catalán, Chiung-Chi Kuo, Ranjani Rajapaksa, Ronald Levy, Shoshana Levy. CD81: A new target for therapy of B cell lymphoma [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B061.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.IMM2016-B061
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2732517-9
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