Human cytotoxic T lymphocyte

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P16-23. Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance

P16-23. Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance

Address: 1 University of Mainz, Mainz, Germany, 2 INSERM, Unité 580, Université Paris-Descartes, Paris, France, 3 University of Copenhagen, Copenhagen, Denmark, 4 Rigshospitalet, The National University Hospital, Copenhagen, Denmark, 5 Oxford University, Oxford, UK and 6 Wellcome Trust Centre for Human Genetics, Oxford University, Oxford, UK * Corresponding author

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Polyoxidonium® Activates Cytotoxic Lymphocyte Responses Through Dendritic Cell Maturation: Clinical Effects in Breast Cancer

Polyoxidonium® Activates Cytotoxic Lymphocyte Responses Through Dendritic Cell Maturation: Clinical Effects in Breast Cancer

RESULTS Effects of PO in Patients With Breast Cancer We selected a cohort of 20 female patients with a mean age of 53.5 years (range 32–78). The first biopsy at day O showed that they had diverse TNM scores and that the majority had infiltrative ductal carcinoma (Table 1). We treated patients intramuscularly with PO for 1 week and obtained a second biopsy at day 8. Among the patients, six demonstrated pathological changes after surgery compared to results before surgery (Table 2). Responding patients had diverse TNM scores, estrogen and progesterone receptors, Her2/neu staining, and proliferative indexes (Table 2). One patient had the particularly aggressive triple-negative phenotype, i.e., negative for the receptors for estrogen, progesterone, and Human Epidermal Growth Factor 2 (HER2), and had a high proliferative index as measured by a high proliferation ratio based on Ki-67 staining (Figure 1). She received 1 week of PO treatment and received a radical mastectomy of the left breast with saving of breast muscles. We observed pathomorphosis degree 4 in the post-surgery material
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Lutte d’influence membranaire pour inhiber ou activer le lymphocyte

Lutte d’influence membranaire pour inhiber ou activer le lymphocyte

released from human activated NK lymphocytes and inhibits cell-mediated cytotoxicity. J Immunol 2007 ; 178 : 1293-300. 2. Bensussan A, Gluckman E, el Marsafy S, et al. BY55 monoclonal antibody delineates within human cord blood and bone marrow lymphocytes distinct cell subsets mediating cytotoxic activity. Proc Natl Acad Sci USA 1994 ; 91 : 9136-40.

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Cytotoxic T-lymphocyte-associated protein 4-Ig effectively controls immune activation and inflammatory disease in a novel murine model of leaky severe combined immunodeficiency

Cytotoxic T-lymphocyte-associated protein 4-Ig effectively controls immune activation and inflammatory disease in a novel murine model of leaky severe combined immunodeficiency

CTLA4-Ig meets all of the intervention criteria listed above. First, as a potent suppressive molecule used by Treg cells for immune suppression, 22 CTLA4-Ig can be substitutive for Treg cells. Second, CTLA4-Ig is highly effective at quenching T H 2 re- sponses. 14 Third, CTLA4-Ig effectively competes with CD80/ CD86 for CD28 binding, 15 countering the increased expression of these molecules in lymphopenic dendritic cells. Because bimonthly administration of CTLA4-Ig to Dclre1c leaky mice resolved inflammation, prevented tissue damage, and improved overall survival, the immunologic rationale of CTLA4-Ig selec- tion for murine LS treatment can be regarded as validated. Although abatacept demonstrates high efficiency in rodent studies, when considering clinical translation, additional options become available, with belatacept demonstrating higher affinity toward human CD86. 23
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en fr Influence of hypoxia on tumour cell susceptibility to cytotoxic T lymphocyte mediated lysis Influence de l’hypoxie sur la susceptibilité des cellules tumorales à la lyse induite par les lymphocytes T cytotoxiques

48 IV. ANTI-TUMOR IMMUNE RESPONSE The major feature of the immune system is its ability to recognize “self” from “foreign” and to destroy the latter, potentially dangerous for host homeostasis. In this context, the recognition and elimination of tumor cells, different from their normal counterparts nevertheless self-derived, was controversial for almost a century. Initially proposed by Paul Ehrlich in 1909, who suggested that the immune system could control tumor development [172], the concept of tumor immunosurveillance is now well established [173] [174], and immune response is considered as an important biomarker in cancer [175]. Despite early skepticism, major progress in tumor immunology has ensued since the 1980s, together with growing understanding of the immune system in general and development of new methodologies e.g. hybridoma technology [176], propagation of human DC [177] and T cells [178], discovery of critical reagents e.g. interleukine-2 [179] and establishment of relevant animal models. One of the major breakthroughs came with the identification by Thierry Boon’s group of a tumor Ag recognized by CTL in humans [180], the finding of which stimulated a productive effort to identify numerous tumor-specific and tumor-associated antigens [181]. Soon, the concept of tumor immunogenicity was supported by growing evidence demonstrating that an effective immune response can be elicited against the development of spontaneous and chemically induced tumors [182] [173]. These outcomes revived enthusiasm in the field of tumor immunology and gave rise to discussion about beneficial versus deleterious consequences of immune response to cancer. This led to the re- formulation of the tumor immunosurveillance hypothesis into “immunoediting” theory, which recognized the selective pressure of the immune system on malignant cells resulting in the emergence of resistant variants and tumor escape [173].
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Melanoma Cells Treated with GGTI and IFN-gamma Allow Murine Vaccination and Enhance Cytotoxic Response against Human Melanoma Cells.

Melanoma Cells Treated with GGTI and IFN-gamma Allow Murine Vaccination and Enhance Cytotoxic Response against Human Melanoma Cells.

The specific cytotoxicity observed after co-cultivating PBMC with LB1319-MEL cells pretreated with the combination of hIFN- c and GGTI-298, suggests that these melanoma cells develop the ability to induce a specific anti-tumor immune response in vitro, likely linked to the increased proliferation of specific CD8 T lymphocytes. To test this hypothesis, PBMC from 3 HLA-A0201 HD were twice stimulated in vitro with LB1319-MEL cells pretreated with hIFN-c and/or GGTI-298 as before. The T lymphocyte subpopulations present in the co-culture were then analyzed by flow cytometry. The LB1319-MEL melanoma cell line expresses peptides on the membrane, obtained from MelanA/ MART-1 proteins and associated with HLA-A0201 molecules, in particular the immunodominant peptide EAAGIGILTV [19]. LB1319-MEL specific CD8 T lymphocytes should therefore express TCR specific for this HLA-A0201-presented peptide, which can be labeled with MART-1/HLA-A0201 tetramers. We observed a significant increase of the CD8 subpopulation labeled with these tetramers in the 3 tested donors (Table 2 and illustrated for one HD in Figure 8A). On the contrary, these stimulated PBMC have similar levels of non-specific TCR, detected with EBV/HLA0201 tetramers, whatever the pretreatment of the stimulator LB1319-MEL cells as illustrated in Figure 8B. How- ever, the control PBMC cultures stimulated by an HLA-A0201 EBV immortalized lymphoblastoid cell line (L1-EBV) were strongly positive with these EBV/HLA0201 tetramers (Figure 8B).
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en fr Dissecting early mechanism of melanoma cell resistance to cytotoxic T lymphocyte attack Etude du mécanisme précoce de la résistance des cellules du mélanome à l'attaque des lymphocytes T cytotoxique

88 II- Aim of the study Background: Several lines of evidence indicate that an endogenous immune response against cancer develops in some patients. Tumor-specific CTL expand at relatively high frequency in cancer patients and tumor-infiltrating lymphocytes (TILs), can be isolated and expanded in vitro from a variety of human cancers. Some TILs have specific cytolytic activity for fresh autologous cancer cells. Yet, the effector function of these naturally occurring CTL is often insufficient to achieve clinical remission 285,344,356,399 . These data indicate that local specific immune responses may develop within tumors. Furthermore, tumor-associated antigen (TAA)-specific T cells have been detected in some tumor-infiltrated lymph nodes. These data lend strong support to the premise that the immune system can recognize and respond to endogenous cancer cells but is unable to eradicate it. Moreover, Therapeutic approaches based on adoptive transfer of ex vivo expanded tumor antigen-specific CTL emerged as a promising therapeutic strategies, in particular in melanoma 395,399 . However, these approaches still suffer limited efficacy and need to be improved before reaching high clinical benefits.
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Dissecting early mechanism of melanoma cell resistance to cytotoxic T lymphocyte attack

Dissecting early mechanism of melanoma cell resistance to cytotoxic T lymphocyte attack

88 II- Aim of the study Background: Several lines of evidence indicate that an endogenous immune response against cancer develops in some patients. Tumor-specific CTL expand at relatively high frequency in cancer patients and tumor-infiltrating lymphocytes (TILs), can be isolated and expanded in vitro from a variety of human cancers. Some TILs have specific cytolytic activity for fresh autologous cancer cells. Yet, the effector function of these naturally occurring CTL is often insufficient to achieve clinical remission 285,344,356,399 . These data indicate that local specific immune responses may develop within tumors. Furthermore, tumor-associated antigen (TAA)-specific T cells have been detected in some tumor-infiltrated lymph nodes. These data lend strong support to the premise that the immune system can recognize and respond to endogenous cancer cells but is unable to eradicate it. Moreover, Therapeutic approaches based on adoptive transfer of ex vivo expanded tumor antigen-specific CTL emerged as a promising therapeutic strategies, in particular in melanoma 395,399 . However, these approaches still suffer limited efficacy and need to be improved before reaching high clinical benefits.
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Sequential adjustment of cytotoxic T lymphocyte densities improves efficacy in controlling tumor growth

Sequential adjustment of cytotoxic T lymphocyte densities improves efficacy in controlling tumor growth

plex to extrapolate to clinical settings. To overcome such a technical bottleneck, we designed an agent-based model, calibrated on experimental measurements, which accurately reproduces human CTL/tumor cell interactions taking place within the cul- ture dish. This in silico approach allows to perform data analysis and modeling of in vitro results obtained at the population level and to extrapolate them to the single cell level. It also allows to dissect individual cell behaviors that could not be inferred by standard in vitro assays. Furthermore, various complex scenarios of CTL/target cell interaction (e.g. cytotoxicity assays lasting several days, investigation of a large spectrum of effector/target (E/T) ratios, etc.) can be explored in silico.
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Sequential adjustment of cytotoxic T lymphocyte densities improves efficacy in controlling tumor growth

Sequential adjustment of cytotoxic T lymphocyte densities improves efficacy in controlling tumor growth

by multiple mechanisms of immune cell inhibition 7 , 8 . It is therefore critical to develop an optimized metrics of human CTL efficacy against cancer cells. A better metrics of CTL responses might be instrumental to adapt ther- apeutic strategies based on CTL adoptive transfer and limit tumor escape from immune surveillance 9 . In this context, a key unresolved question concerns the definition of human CTL per capita killing rates. Understanding the inner dynamics of human CTL/tumor cell interaction is indeed crucial to define how efficient individual CTL are when facing cancer cells for a prolonged time. Unfortunately, gaining in vitro data on human CTL per capita killing requires visualization of a large number of individual CTL/target cell interactions using time-lapse microscopy optimized for single cell inspection 10 – 12 . This approach is technically challenging and com-
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Recombinaisons suicides du locus IgH - Quand le lymphocyte B dépose les armes !

Recombinaisons suicides du locus IgH - Quand le lymphocyte B dépose les armes !

Les deux événements, SHM comme CSR, nécessitent la transcrip- tion des régions cibles sous le contrôle d’activateurs situés à l’extrémité 3’ du locus IgH, dans la région 3’ régulatric[r]

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Biophysical mechanisms of lymphocyte adhesion to activated vascular endothelium

Biophysical mechanisms of lymphocyte adhesion to activated vascular endothelium

The expression studies revealed that fluid extracted from the tumor interstitium upregulates specific CAMs on endothelial cells in vitro, which promotes lymphocyte bin[r]

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The endocrine milieu and CD4 T-lymphocyte polarization during pregnancy

The endocrine milieu and CD4 T-lymphocyte polarization during pregnancy

Keywords: progesterone, estradiol, human chorionic gonadotropin, luteinizing hormone, regulatoryT cells,T helper 17 cells, pregnancy INTRODUCTION Pregnancy constitutes an immunological paradox since it implies that a fetus semi-antigenically distinct from the mother is not rejected by her immune system from embryo implantation to delivery. Peter Medawar was the first to consider the fetus as a semi- allograft and to suggest a major role for the immune system in ensuring maintenance of pregnancy ( 1 ). Since then, the establish- ment of tolerance of mother’s immune system to the embryonic and fetal semi-allograft has become the focus of intensive research. Uterine Natural Killer (uNK) cells have been demonstrated to be main actors of pregnancy with their effects on angiogenesis, vas- cular remodeling, trophoblast invasion, and cytokine production ( 2 , 3 ). CD4+ T cells are also important actors in the establishment of a «pregnancy favorable environment», and the Th1/Th2 para- digm has been prevailing for years. Briefly, feto-maternal accep- tance was explained by Th2 profile predominance essential for pregnancy while pro-inflammatory Th1 cytokines were shown to be downregulated ( 4 ). This Th1/Th2 paradigm has been expanded
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Highly Cytotoxic Copper(II) Terpyridine Complexes as Anticancer Drug Candidates

Highly Cytotoxic Copper(II) Terpyridine Complexes as Anticancer Drug Candidates

ABSTRACT Cancer is one of the deadliest diseases worldwide. Chemotherapy remains one of the frequently applied treatment modalities in the clinics. However, as the currently applied agents are associated with severe side effects, scientists are searching for novel chemotherapeutic drugs. Within the last decades, Cu(II) polypyridine complexes have received increasing attention as potential anticancer drug candidates. Herein, the biological activity of terminally functionalised mono- and bis-coordinated Cu(II)-2,2´:6´,2´´-terpyridine complexes have been investigated. The bis-coordinated compounds were found to have a cytotoxic effect in the nanomolar range in human adenocarcinomic alveolar basal epithelial cells. Promisingly, the complexes were equally active in the corresponding cisplatin resistant cell line, indicating that they could potentially be useful for the treatment of drug resistant tumours.
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Autophagy and CD4+ T lymphocyte destruction by HIV-1.

Autophagy and CD4+ T lymphocyte destruction by HIV-1.

9. Debatin KM, Fahrig-Faissner A, Enenkel-Stoodt S, Kreuz W, Benner A, Krammer PH. High expression of APO-1 (CD95) on T lymphocytes from human immunodeficiency virus-1-infected children. Blood 1994; 83:3101-3. 10. Finkel TH, Tudor-Williams G, Banda NK, Cotton MF, Curiel T, Monks C, Baba TW, Ruprecht RM, Kupfer A. Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nat Med 1995; 1:129-34.

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The role of SHIP1 in T-lymphocyte life and death

The role of SHIP1 in T-lymphocyte life and death

Tel: + 32 4 366 24 26, Fax: + 32 4 366 99 33 Key Words: SHIP-1, T lymphocyte, PI3K, NF-κB, apoptosis, proliferation. ABBREVIATIONS PI3K: phosphoinositide 3-kinase; ITIM: immuno-receptor tyrosine inhibition motif; ITAM: immuno-receptor tyrosine activation motif; Dok: downstream of tyrosine kinase; FcR: IgG Fc receptor; PLCγ: phospholipase C gamma; BTK: Burton’s tyrosine kinase; GSK-3β: glycogen synthase kinase 3 beta; KLF2: Krüppel-like factor 2; NF-κB: nuclear factor κB; IκBα : Inhibitor of κB alpha; TGFβ: transforming growth factor beta.

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New low-cytotoxic P-containing nitrones targeting mitochondria

New low-cytotoxic P-containing nitrones targeting mitochondria

Figure 1: Structure of new low-cytotoxic nitrones targeting mitochondria New mito-PPNs were good EPR probes for biologically-relevant carbon- and oxygen-derived free radicals, efficiently inhibited superoxide in vitro and showed low toxicity on cultured fibroblasts. Their mitochondrial permeation was assessed by 31 P NMR spectroscopy on isolated rat livers. Altogether, mito-PPNs could be promising tools to elucidate radical mechanisms impacting mitochondria, as well as low toxic mitochondria targeted antioxidants.

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[Autophagy and CD4 T lymphocyte destruction by HIV-1]

[Autophagy and CD4 T lymphocyte destruction by HIV-1]

Autophagy and CD4 T lymphocyte destruction by HIV-1 REMERCIEMENTS Ce travail a été soutenu par le Centre National de la Recherche Scientifique (CNRS), l’Université Montpellier I (UMI), Sidaction et l’Agence Nationale de Recherche sur le sida (ANRS).

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Actin nucleation at the centrosome controls lymphocyte polarity.

Actin nucleation at the centrosome controls lymphocyte polarity.

The term immune synapse refers to the zone of tight interaction that forms between lymphocytes and antigen-presenting cells towards which the centrosome polarizes 9 . It is viewed as a signalling platform where both exocytotic and endocytotic events needed for lymphocytes to perform their specific effector function take place 10 . These include the secretion of granules in both cytotoxic lymphocytes and natural killer cells 11 , of cytokine-loaded vesicles in helper T cells 12,13 and of hydrolase-containing lysosomes in B cells 5,14 . Hence, centrosome polarization emerges as pivotal in the regulation of immunity, stressing the need to unravel the underlying molecular mechanisms. In that regard, PKC and Cdc42 signalling molecules as well as the microtubule minus- end motor Dynein were shown to regulate centrosome repositioning at the synapse of both B and T lymphocytes 14–20 . Regarding the actin cytoskeleton, Arp2/3-dependent nucleation of F-actin was shown to be dispensable for centrosome polarization in T lymphocytes, which rather requires the activity of Formins 21 . In general, whether and how centrosome-intrinsic components regulate its ability to polarize remains unexplored.
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Chemical Library Screening and Structure-Function Relationship Studies Identify Bisacodyl as a Potent and Selective Cytotoxic Agent Towards Quiescent Human Glioblastoma Tumor Stem-Like Cells

Chemical Library Screening and Structure-Function Relationship Studies Identify Bisacodyl as a Potent and Selective Cytotoxic Agent Towards Quiescent Human Glioblastoma Tumor Stem-Like Cells

S1 Methods. Expression of stemness, pluripotency and differentiation markers in prolifer- ating and quiescent GSCs. The expression levels (mRNA) of 90 genes enclosing stemness, pluripotency and differentiation markers and 6 endogenous controls (see S2 Table ) were stud- ied in both proliferating and quiescent TG1 and OB1 GSCs using the real-time PCR based Taq- Man Human Stem Cell Pluripotency Array (Applied Biosystems, Life Technologies). Briefly, total RNA was extracted using TriReagent (Invitrogen). cDNA synthesis was performed with 10 μg of total RNA at 37°C for 2 hours using the High Capacity cDNA Archive kit (Applied Biosystems, Life Technologies). Quantitative PCR was performed using the ABI Prism 7900HT Sequence Detection System (Applied Biosystems). Cycle threshold (Ct) values were measured. Ribosomal RNA18s was used as housekeeping gene. Expression levels of Nanog, GBX2 and IFITM1 were also verified using individual TaqMan gene expression assays from Applied Bio- systems, Life Technologies as described in the Materials and Methods section. FACS analysis was used to study Nanog protein expression in proliferating and quiescent TG1 and OB1 GSCs. Neurospheres were dissociated and cells were resuspended in PBS. Fixable viability Dye eFluor 450 labeling (eBioscience) was performed to irreversibly label dead cells. Following washing with PBS, cells were fixed with 2% paraformaldehyde in PBS (10 min at room temper- ature). Permeabilization (5 min at room temperature) was performed in the presence of 0.1% of saponin and cells were then washed once in HBSS buffer containing saponin (0.1%). Non- specific sites were blocked in PBS solution containing 3% BSA and 2.5% of fetal bovine serum for 30 min at room temperature. Primary antibody labeling (anti-Nanog rabbit polyclonal; Abcam; 1/200) was performed overnight at 4°C. Secondary antibody incubation (1 hour at room temperature) was followed by FACS analysis. Cells labeled with the secondary antibody in the absence of the primary antibody were used as negative controls.
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