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Xiaole Zhang, Lei Gao, Kai Meng, Chunting Han, Qiang Li, Zhenjun Feng, Lei Chen
Multiple myeloma (MM) is an incurable cancer characterized by the development of malignant plasma cells. The CD8 T cell-mediated cytotoxicity is considered a major player in antitumor immunity, but in MM patients, the CD8 T cells displayed senescence markers and were functionally impaired. To investigate whether cytotoxic CD4 T cells could act as a treatment alternative in MM, we examined the frequency and function of naturally occurring cytotoxic CD4 T cells in MM patients. The cytotoxic CD4 T cells were identified as granzyme-A, granzyme B-, and perforin-expressing CD4 T cells, and their frequencies were significantly upregulated in MM patients when compared with healthy controls...
February 12, 2018: Cellular Immunology
Thomas D Duensing, Susan R Watson
A useful feature of therapeutic antibodies is the ability to kill the cells to which they bind. Antibodies are capable of mediating cell killing in a variety of ways. Apoptosis, complement-mediated mechanisms, and antibody-dependent cellular cytotoxicity (ADCC) are all effects that can be assayed to characterize lead antibody candidates. Extensive, multidose characterizations of a series of candidates can be performed in a short amount of time using assays developed for high-throughput flow cytometry systems...
February 1, 2018: Cold Spring Harbor Protocols
Grant S Schulert, Scott W Canna
Hyperferritinemia and pronounced hemophagocytosis help distinguish a subset of patients with a particularly inflammatory and deadly systemic inflammatory response syndrome. Two clinically similar disorders typify these hyperferritinemic syndromes: hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). HLH is canonically associated with a complete disturbance of perforin/granzyme-mediated cytotoxicity, whereas MAS occurs in the context of the related rheumatic diseases systemic juvenile idiopathic arthritis (SJIA) and adult-onset Still's disease (AOSD), with associated IL-1 family cytokine activation...
February 6, 2018: International Immunology
Kristofor K Ellestad, Govindarajan Thangavelu, Yohannes Haile, Jiaxin Lin, Louis Boon, Colin C Anderson
Lymphopenia can result from various factors, including viral infections, clinical interventions, or as a normal property of the fetal/neonatal period. T cells in a lymphopenic environment undergo lymphopenia-induced proliferation (LIP) to fill the available "niche" as defined by peptide-MHC and homeostatic cytokine resources. We recently reported systemic autoimmunity following reconstitution of the lymphoid compartment of Rag1-/- mice with PD-1-/- hematopoietic stem cells or by transfer of thymocytes, but not splenocytes, suggesting that programmed death-1 (PD-1) plays a crucial role in controlling recent thymic emigrants (RTE) and preventing autoimmunity upon their LIP...
2018: Frontiers in Immunology
Amelia J Brennan, Ruby H P Law, Paul J Conroy, Tahereh Noori, Natalya Lukoyanova, Helen Saibil, Hideo Yagita, Annette Ciccone, Sandra Verschoor, James C Whisstock, Joseph A Trapani, Ilia Voskoboinik
The pore forming, Ca2+-dependent protein, perforin, is essential for the function of cytotoxic lymphocytes, which are at the frontline of immune defence against pathogens and cancer. Perforin is a glycoprotein stored in the secretory granules prior to release into the immune synapse. Congenital perforin deficiency causes fatal immune dysregulation, and is associated with various haematological malignancies. At least 50% of pathological missense mutations in perforin result in protein misfolding and retention in the endoplasmic reticulum...
February 7, 2018: Cell Death and Differentiation
Peng Qian, Yong-Wen Zhang, Zhong-Hai Zhou, Jun-Quan Liu, Su-Yang Yue, Xiang-Li Guo, Lei-Qing Sun, Xiao-Ting Lv, Jian-Qun Chen
OBJECTIVE: To explore the effect and mechanism of artesunate on γδ T cell-mediated antitumor immune responses against hepatoma carcinoma cells (HepG2) in vitro. METHODS: Human γδ T cells or HepG2 were respectively treated with artesunate, subjected to co-culture as appropriate, and the following assays were subsequently conducted: CCK8 to examine cell viability; LDH release assay to detect the killing effect of γδ T cells on HepG2 cells; flow cytometry to examine the expression of perforin (PFP) and granzyme B (GraB) of γδ T cells; ELISA to evaluate the levels of TGF-β1 and IL-10 in the collected supernatant of HepG2 cells pretreated with artesunate; and Western blot analysis to examine Fas, FasL, STAT3, p-STAT3 expression of HepG2 cells induced by artesunate...
February 6, 2018: Immunopharmacology and Immunotoxicology
Aurélie Durgeau, Yasemin Virk, Stéphanie Corgnac, Fathia Mami-Chouaib
Recent advances in cancer treatment have emerged from new immunotherapies targeting T-cell inhibitory receptors, including cytotoxic T-lymphocyte associated antigen (CTLA)-4 and programmed cell death (PD)-1. In this context, anti-CTLA-4 and anti-PD-1 monoclonal antibodies have demonstrated survival benefits in numerous cancers, including melanoma and non-small-cell lung carcinoma. PD-1-expressing CD8+ T lymphocytes appear to play a major role in the response to these immune checkpoint inhibitors (ICI). Cytotoxic T lymphocytes (CTL) eliminate malignant cells through recognition by the T-cell receptor (TCR) of specific antigenic peptides presented on the surface of cancer cells by major histocompatibility complex class I/beta-2-microglobulin complexes, and through killing of target cells, mainly by releasing the content of secretory lysosomes containing perforin and granzyme B...
2018: Frontiers in Immunology
Jiao Chen, Yaping Fan, Bomiao Cui, Xiaoying Li, Yu Yu, Yue Du, Qianming Chen, Yun Feng, Ping Zhang
γδT cells function in the regulation of T-cell activation in cancer and have been identified as a novel target for cancer immunotherapy. Activated γδT cells release a series of cytotoxic molecules-including granulysin, perforin, Fas/Fas ligand (Fas-L), and granzymes A and B-to kill target cells. Our previous research has shown that high mobility group nucleosomal-binding domain 2 (HMGN2), which is expressed at a high level in activated CD8T cells, is an antitumor effector molecule of CD8T cells. In the present study, we examined the expression and antitumor effects of HMGN2 in γδT cells...
February 2, 2018: Journal of Immunotherapy
Irina Obleukhova, Nataliya Kiryishina, Svetlana Falaleeva, Julia Lopatnikova, Vasiliy Kurilin, Vadim Kozlov, Aleksander Vitsin, Andrey Cherkasov, Ekaterina Kulikova, Sergey Sennikov
Cancer is associated with a reduction in immature and mature circulating dendritic cells (DCs), and with an impaired migratory capacity, compared with healthy donors. Therefore, modern approaches to the in vitro generation of DCs loaded with tumor antigens and their use for inducing antitumor immune responses in vivo are being investigated. The purpose of the present study was to investigate the phenotypic and functional characteristics of peripheral blood DC subsets in patients with non-small cell lung cancer (NSCLC), and the development of an antitumor cytotoxic response by mononuclear cells (MNCs) from patients using in vitro generated antigen-primed DCs...
January 2018: Oncology Letters
Shuguo Wang, Fenghai Liu, Hongguo Zhao
To investigate the contribution and mechanism of eosinophil granulocytes and NK cells-mediated cytotoxicity to the pathogenesis of ITP. Mononuclear cells and platelets were prepared from the bone marrow of 16 ITP patients and 10 healthy controls. Separately, eosinophil granulocytes and NK cells were selected with magnetic microbeads. As the target cells, the autologous platelets were cultured with eosinophil granulocytes and NK cells respectively for 6 h and then stained with annexin V. Ratio of platelets expressing annexin V was determined by flow cytometry...
January 2018: Indian Journal of Hematology & Blood Transfusion
Rika Fujii, Caroline Jochems, Sarah R Tritsch, Hing C Wong, Jeffrey Schlom, James W Hodge
Natural killer (NK) cells are innate cytotoxic lymphocytes that play a fundamental role in the immunosurveillance of cancers. NK cells of cancer patients exhibit impaired function mediated by immunosuppressive factors released from the tumor microenvironment (TME), such as transforming growth factor (TGF)-β1. An interleukin (IL)-15 superagonist/IL-15 receptor α fusion complex (IL-15SA/IL-15RA; ALT-803) activates the IL-15 receptor on CD8 T cells and NK cells, and has shown significant anti-tumor activity in several in vivo studies...
February 1, 2018: Cancer Immunology, Immunotherapy: CII
Padmaja Paidipally, Deepak Tripathi, Abhinav Van, Rajesh Kumar Radhakrishnan, Rohan Dhiman, Sambasivan Venkatasubramanian, Kamakshi P Devalraju, Amy R Tvinnereim, Vijaya Lakshmi Valluri, Ramakrishna Vankayalapati
In the current study, we determined the effects of interleukin (IL)-21 on human natural killer (NK) cells and monocyte responses during Mycobacterium tuberculosis (Mtb) infection. We found that Mtb stimulated CD4+ and NKT cells from healthy individuals with latent tuberculosis infection (LTBI+) are major sources of IL-21. CD4+ cells from tuberculosis patients secreted less IL-21 than did CD4+ cells from healthy LTBI+ individuals. IL-21 had no direct effect on Mtb stimulated monocytes. IL-21 activated NK cells produced IFN-γ, perforin, granzyme B and granulysin; lysed Mtb infected monocytes; and reduced Mtb growth...
January 30, 2018: Journal of Infectious Diseases
Karine Chemin, Daniel Ramsköld, Lina-Marcela Diaz-Gallo, Jessica Herrath, Miranda Houtman, Karolina Tandre, Lars Rönnblom, Anca Catrina, Vivianne Malmström
The presence of the PTPN22 risk allele (1858T) is associated with several autoimmune diseases including rheumatoid arthritis (RA). Despite a number of studies exploring the function of PTPN22 in T cells, the exact impact of the PTPN22 risk allele on T-cell function in humans is still unclear. In this study, using RNA sequencing, we show that, upon TCR-activation, naïve human CD4+ T cells homozygous for the PTPN22 risk allele overexpress a set of genes including CFLAR and 4-1BB, which are important for cytotoxic T-cell differentiation...
January 31, 2018: European Journal of Immunology
Agnieszka Witalisz-Siepracka, Dagmar Gotthardt, Michaela Prchal-Murphy, Zrinka Didara, Ingeborg Menzl, Daniela Prinz, Leo Edlinger, Eva Maria Putz, Veronika Sexl
Cyclin-dependent kinase 8 (CDK8) is a member of the transcription-regulating CDK family. CDK8 activates or represses transcription by associating with the mediator complex or by regulating transcription factors. Oncogenic activity of CDK8 has been demonstrated in several cancer types. Targeting CDK8 represents a potential therapeutic strategy. Because knockdown of CDK8 in a natural killer (NK) cell line enhances cytotoxicity and NK cells provide the first line of immune defense against transformed cells, we asked whether inhibiting CDK8 would improve NK-cell antitumor responses...
January 31, 2018: Cancer Immunology Research
Mehdi Najar, Mohammad Fayyad-Kazan, Nathalie Meuleman, Dominique Bron, Hussein Fayyad-Kazan, Laurence Lagneaux
Due to their easier isolation, multilineage potential, and immunomodulatory capacity, Wharton's Jelly-derived mesenchymal stromal cells (WJ-MSCs) exhibit promising efficacy in the field of regenerative medicine and immunotherapy. Characterization of WJ-MSCs-natural killer (NK) cells crosstalk is required for ameliorating the medicinal value of WJ-MSCs. Here, we revealed that the outcome of WJ-MSCs-NK cells crosstalk varied according to the type of cytokines (IL-2, IL-12, IL-15 and IL-21) utilized to activate NK cells...
January 30, 2018: Molecular and Cellular Biochemistry
Michael Koldehoff, Monika Lindemann, Stefan R Ross, Ahmet H Elmaagacli
Cytomegalovirus (HCMV) reactivation is found frequently after allogeneic hematopoietic stem cell transplantation (alloSCT) and is associated with an increased treatment-related mortality. Recent reports suggest a link between HCMV and a reduced risk of cancer progression in patients with acute leukemia or lymphoma after alloSCT. Here we show that HCMV can inhibit the proliferation of the acute myeloid leukemia cell line Kasumi-1 and the promyeloid leukemia cell line NB4. HCMV induced a significant up-regulation of HLA-class-II-molecules, especially HLA-DR expression and an increase of apoptosis, granzyme B, perforin and IFN-γ secretion in Kasumi-1 cells cocultured with peripheral blood mononuclear cells (PBMCs)...
2018: PloS One
Marcus Lettau, Fred Armbrust, Katharina Dohmen, Lisann Drews, Tobias Poch, Michelle Dietz, Dieter Kabelitz, Ottmar Janssen
It is widely accepted that cytotoxic T and NK cells store effector proteins including granzymes, perforin and FasL in intracellular granules, often referred to as secretory lysosomes. Upon target cell encounter, these organelles are transported to the cytotoxic immunological synapse, where they fuse with the plasma membrane to release the soluble effector molecules and to expose transmembrane proteins including FasL on the cell surface. We previously described two distinct species of secretory vesicles in T and NK cells that differ in size, morphology and protein loading, most strikingly regarding FasL and granzyme B...
January 24, 2018: International Immunology
Stanislaw Schmidt, Annalisa Condorelli, Antonia Koltze, Thomas Lehrnbecher
There is growing evidence that Natural Killer (NK) cells exhibit in vitro activity against both Aspergillus and non-Aspergillus molds. Cytotoxic molecules such as NK cell-derived perforin seem to play an important role in the antifungal activity. In addition, NK cells release a number of cytokines upon stimulation by fungi, which modulate both innate and adaptive host immune responses. Whereas the in vitro data of the antifungal activity of NK cells are supported by animal studies, clinical data are scarce to date...
May 19, 2017: Journal of Fungi (Basel, Switzerland)
Alex R Johns, Michelle A Henstridge, Melissa J Saligari, Karyn A Moore, James C Whisstock, Coral G Warr, Travis K Johnson
Patterning of the Drosophila embryonic termini by the Torso (Tor) receptor pathway has long served as a valuable paradigm for understanding how Receptor Tyrosine Kinase (RTK) signalling is controlled. However, the mechanisms that underpin the control of Tor signalling remain to be fully understood. In particular, it is unclear how the Perforin-like protein Torso-like (Tsl) localises Tor activity to the embryonic termini. To shed light on this, together with other aspects of Tor pathway function, we conducted a genome-wide screen to identify new pathway components that operate downstream of Tsl...
January 23, 2018: G3: Genes—Genomes—Genetics
Sujal Ghosh, Marlene Carmo, Miguel Calero-Garcia, Ida Ricciardelli, Juan Carlos Bustamante Ogando, Michael P Blundell, Axel Schambach, Philip G Ashton-Rickardt, Claire Booth, Stephan Ehl, Kai Lehmberg, Adrian J Thrasher, H Bobby Gaspar
BACKGROUND: Mutations in the PRF1 gene account for up to 58% of familial haemophagocytic lymphohistiocytosis (FHL) syndromes. The resulting defects in effector cell cytotoxicity lead to hypercytokinaemia and hyperactivation with inflammation in various organs. OBJECTIVE: To determine whether autologous gene corrected T cells can restore cytotoxic function, reduce disease activity and prevent haemophagocytic lymphohistiocytosis (HLH) symptoms in in vivo models. METHODS: We developed a gammaretroviral vector to transduce murine CD8-T cells in the prf-/- mouse model...
January 17, 2018: Journal of Allergy and Clinical Immunology
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