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NK-cell and T-cell functions in patients with breast cancer: effects of surgery and adjuvant chemo- and radiotherapy

Mozaffari, F; Lindemalm, C; Choudhury, A; Granstam-Björneklett, H; Helander, I; Lekander, M; Mikaelsson, E; Nilsson, B; Ojutkangas, M-L; Österborg, A; Bergkvist, L; Mellstedt, H
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
45.77%
Breast cancer is globally the most common malignancy in women. Her2-targeted monoclonal antibodies are established treatment modalities, and vaccines are in late-stage clinical testing in patients with breast cancer and known to promote tumour-killing through mechanisms like antibody-dependent cellular cytotoxicity. It is therefore increasingly important to study immunological consequences of conventional treatment strategies. In this study, functional tests and four-colour flow cytometry were used to detect natural killer (NK)-cell functions and receptors as well as T-cell signal transduction molecules and intracellular cytokines in preoperative breast cancer patients, and patients who had received adjuvant radiotherapy or adjuvant combined chemo-radiotherapy as well as in age-matched healthy controls. The absolute number of NK cells, the density of NK receptors as well as in vitro quantitation of functional NK cytotoxicity were significantly higher in preoperative patients than the post-treatments group and controls. A similar pattern was seen with regard to T-cell signalling molecules, and preoperative patients produced significantly higher amounts of cytokines in NK and T cells compared to other groups. The results indicate that functions of NK and T cells are well preserved before surgery but decrease following adjuvant therapy...

CXCR4–CCR5: A couple modulating T cell functions

Contento, Rita Lucia; Molon, Barbara; Boularan, Cedric; Pozzan, Tullio; Manes, Santos; Marullo, Stefano; Viola, Antonella
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
45.75%
Chemokines and their receptors direct leukocyte migration among blood, lymph and tissues. Evidence has recently accumulated that, besides their chemotactic functions, chemokine receptors are highly versatile players that fine tune immune responses. During human T cell activation by antigen-presenting cells, the chemokine receptors CCR5 and CXCR4 are recruited into the immunological synapse, where they deliver costimulatory signals. However, the molecular mechanisms allowing signaling versatility of chemokine receptors are unknown. Here, we describe the functional interaction between CXCR4 and CCR5 to exert specific biological functions and modulate T lymphocyte responses. We demonstrate that simultaneous expression and cooperation between CCR5 and CXCR4 are required for chemokine-induced T cell costimulation at the immunological synapse. In addition, we provide evidence for a physical association of the two receptors in a signaling complex that activates distinct T cell functions. We suggest that cooperation between receptors represents one key strategy for the functional plasticity of chemokines.

Chemical Genetics Reveals Bacterial and Host Cell Functions Critical for Type IV Effector Translocation by Legionella pneumophila

Charpentier, Xavier; Gabay, Joëlle E.; Reyes, Moraima; Zhu, Jing W.; Weiss, Arthur; Shuman, Howard A.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
45.75%
Delivery of effector proteins is a process widely used by bacterial pathogens to subvert host cell functions and cause disease. Effector delivery is achieved by elaborate injection devices and can often be triggered by environmental stimuli. However, effector export by the L. pneumophila Icm/Dot Type IVB secretion system cannot be detected until the bacterium encounters a target host cell. We used chemical genetics, a perturbation strategy that utilizes small molecule inhibitors, to determine the mechanisms critical for L. pneumophila Icm/Dot activity. From a collection of more than 2,500 annotated molecules we identified specific inhibitors of effector translocation. We found that L. pneumophila effector translocation in macrophages requires host cell factors known to be involved in phagocytosis such as phosphoinositide 3-kinases, actin and tubulin. Moreover, we found that L. pneumophila phagocytosis and effector translocation also specifically require the receptor protein tyrosine phosphate phosphatases CD45 and CD148. We further show that phagocytosis is required to trigger effector delivery unless intimate contact between the bacteria and the host is artificially generated. In addition, real-time analysis of effector translocation suggests that effector export is rate-limited by phagocytosis. We propose a model in which L. pneumophila utilizes phagocytosis to initiate an intimate contact event required for the translocation of pre-synthesized effector molecules. We discuss the need for host cell participation in the initial step of the infection and its implications in the L. pneumophila lifestyle. Chemical genetic screening provides a novel approach to probe the host cell functions and factors involved in host–pathogen interactions.

Secretion of VEGF by oral squamous cell carcinoma cells skews endothelial cells to suppress T-cell functions

Mulligan, Jennifer K.; Day, Terry A.; Gillespie, M. Boyd; Rosenzweig, Steven A.; Young, M. Rita I.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
45.75%
Patients with oral squamous cell carcinoma (OSCC) have severe defects in anti-tumor immune functions. Endothelial cells are potential regulators of immune cell functions and have therefore been examined to determine their role in tumor-induced immune suppression. The present studies showed that supernatants from endothelial cells exposed to OSCC-conditioned media (EndoOSCC-sup) had elevated levels of the immune suppressive products PGE2 and VEGF as compared to supernatants from endothelial cells treated with media alone (EndoMedia) or with keratinocyte-conditioned media (EndoKer-sup). Antibody neutralization of OSCC-derived VEGF prevented tumor-conditioned media from inducing endothelial cells to increase production of PGE2 and VEGF. Furthermore, treatment of T-cells with supernatants from EndoOSCC-sup resulted in diminished T-cell proliferation and decreased IFN-γ production, when compared to T-cells treated with media or supernatants from EndoMedia or EndoKer-sup controls. T-cell levels of granzyme B and perforin were reduced after treatment with supernatant from EndoOSCC-sup compared to control treatments. Addition of VEGF neutralizing antibody to the OSCC-conditioned media prevented endothelial cells from being skewed to downregulate T-cell proliferation and production of IFN-γ...

Modification of Collagen IV by Glucose or Methylglyoxal Alters Distinct Mesangial Cell Functions

Pozzi, Ambra; Zent, Roy; Chetyrkin, Sergei; Borza, Corina; Bulus, Nada; Chuang, Peale; Chen, Dong; Hudson, Billy; Voziyan, Paul
Fonte: American Society of Nephrology Publicador: American Society of Nephrology
Tipo: Artigo de Revista Científica
Publicado em /10/2009 EN
Relevância na Pesquisa
45.77%
Diabetic nephropathy (DN) affects both glomerular cells and the extracellular matrix (ECM), yet the pathogenic mechanisms involving cell-matrix interactions are poorly understood. Glycation alters integrin-dependent cell-ECM interactions, and perturbation of these interactions results in severe renal pathology in diabetic animals. Here, we investigated how chemical modifications of the ECM by hyperglycemia and carbonyl stress, two major features of the diabetic milieu, affect mesangial cell functions. Incubation of collagen IV with pathophysiological levels of either the carbonyl compound methylglyoxal (MGO) or glucose resulted in modification of arginine or lysine residues, respectively. Mouse mesangial cells plated on MGO-modified collagen IV showed decreased adhesion and migration. Cells plated on glucose-modified collagen IV showed reduced proliferation and migration and increased collagen IV production. Inhibiting glucose-mediated oxidative modification of collagen IV lysine residues rescued the alterations in cell growth, migration, and collagen synthesis. We propose that diabetic ECM affects mesangial cell functions via two distinct mechanisms: modification of arginine residues by MGO inhibits cell adhesion, whereas oxidative modification of lysine residues by glucose inhibits cell proliferation and increases collagen IV production. These mechanisms may contribute to mesangial cell hypertrophy and matrix expansion in DN.

SALUTARY EFFECTS OF 17β-ESTRADIOL ON PEYER’S PATCH T CELL FUNCTIONS FOLLOWING TRAUMA-HEMORRHAGE

Kawasaki, Takashi; Suzuki, Takao; Choudhry, Mashkoor A.; Bland, Kirby I.; Chaudry, Irshad H.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
45.79%
Although 17β-estradiol (E2) administration following trauma-hemorrhage (T-H) improves immune functions in male rodents, it remains unclear whether E2 has salutary effects on Peyer’s patch (PP) T cell functions. We hypothesized that T-H induces PP T cell dysfunction and E2 administration following T-H will improve PP T cell function. T-H was induced in male C3H/HeN mice (6–8 weeks) by midline laparotomy and ~90 min of hemorrhagic shock (blood pressure 35 mmHg), followed by fluid resuscitation (4x the shed blood volume in the form of Ringer’s lactate). Estrogen receptor (ER)-α agonist propyl pyrazole triol (PPT; 5 μg/kg), ER-β agonist diarylpropionitrile (DPN; 5 μg/kg), E2 (50 μg/kg), or vehicle was injected subcutaneously at resuscitation onset. Two hrs later, mice were sacrificed and PP T cells isolated. PP T cell capacity to produce cytokines in response to in vitro stimulation, PP T cell proliferation and MAPK (p38, ERK-1/2, JNK) activation were measured. Results indicate PP T cell proliferation, cytokine production and MAPK activation decreased significantly following T-H. E2, PPT or DPN administration normalized these parameters. Since PPT or DPN administration following T-H was effective in normalizing PP T cell functions...

Lidocaine suppresses mouse Peyer’s patch T cell functions and induces bacterial translocation

Kawasaki, Takashi; Kawasaki, Chika; Sata, Takeyoshi; Chaudry, Irshad H.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
45.79%
The gastrointestinal mucosa is an important route of entry for microbial pathogens. The immune cells of Peyer’s patch (PP) compartments contribute to the active immune response against infection. Although local anesthetics are widely used in clinical practice, it remains unclear whether local anesthetics such as lidocaine affect PP T cell functions. The aim of this study was to examine if lidocaine has any effects on mouse PP T cell functions. To test this, freshly isolated mouse Peyer’s patch T cells were incubated with lidocaine. The effects of lidocaine on concanavalin A-stimulated PP T cell proliferation and cytokine production were assessed. The effect of lidocaine on PP T cell mitogen-activated protein kinase (MAPK) activation was also assessed. The results indicate that lidocaine suppresses cell proliferation, cytokine production, and MAPK activation in PP T cells. Furthermore, we found that the chronic in vivo exposure to lidocaine increases bacterial accumulation in PP. The enhanced immunosuppressive effects of lidocaine on PP T cell functions could contribute to the host’s enhanced susceptibility to infection.

Rapid clearance of herpes simplex virus type 2 by CD8+ T cells requires high level expression of effector T cell functions

Nelson, Michelle H.; Bird, Melanie D.; Chu, Chin-Fun; Johnson, Alison J.; Friedrich, Brian M.; Allman, Windy R.; Milligan, Gregg N.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
45.75%
CD8+ T cells are important for resolution of HSV-2 lesions from the female genital epithelium. It is uncertain whether optimal clearance of viruses such as HSV-2 that cause a limited, non-systemic infection solely requires expression of effector functions by infiltrating CD8+ T lymphocytes, or if the clearance rate is reflective of the expression level of critical effector functions. To address this, CD8+ T cells from normal OT-I mice or OT-I mice deficient in IFNγ (IFNγ−/−) or the IFNγ receptor (IFNγR−/−) were activated in vitro in the presence of IFNγ or IL-4 to generate a series of effector populations (Tc1 and Tc2-like respectively) that secreted different levels of IFNγ and expressed different levels of HSV-specific cytolytic function. Compared with Tc1 cells, Tc2-like cells produced the type 2 cytokines IL-4 and IL-5, exhibited decreased IFNγ secretion, diminished proliferation in vitro, and decreased antigen-specific cytolysis in vivo. Clearance of an ovalbumin-expressing HSV-2 strain (HSV-2 tk− OVA) by adoptively transferred Tc2-like cells was delayed relative to Tc1 cell recipients. Because donor Tc2-like cells proliferated in vivo and infiltrated the infected genital epithelium similar to Tc1 cells, the diminished virus clearance by Tc2-like effector cells correlated with reduced expression of critical effector functions. Together...

CDK-Mediated Regulation of Cell Functions via c-Jun Phosphorylation and AP-1 Activation

Vanden Bush, Tony J.; Bishop, Gail A.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 29/04/2011 EN
Relevância na Pesquisa
45.77%
Cyclin-dependent kinases (CDKs) and their targets have been primarily associated with regulation of cell-cycle progression. Here we identify c-Jun, a transcription factor involved in the regulation of a broad spectrum of cellular functions, as a newly recognized CDK substrate. Using immune cells from mouse and human, and several complementary in vitro and in vivo approaches including dominant negative protein expression, pharmacologic inhibitors, kinase assays and CDK4 deficient cells, we demonstrate the ability of CDK4 to phosphorylate c-Jun. Additionally, the activity of AP-1, a ubiquitous transcription factor containing phosphorylated c-Jun as a subunit, was inhibited by abrogating CDK4. Surprisingly, the regulation of c-Jun phosphorylation by CDK4 occurred in non-dividing cells, indicating that this pathway is utilized for cell functions that are independent of proliferation. Our studies identify a new substrate for CDK4 and suggest a mechanism by which CDKs can regulate multiple cellular activation functions...

Neem Leaf Glycoprotein Partially Rectifies Suppressed Dendritic Cell Functions and Associated T Cell Efficacy in Patients with Stage IIIB Cervical Cancer ▿

Roy, Soumyabrata; Goswami, Shyamal; Bose, Anamika; Chakraborty, Krishnendu; Pal, Smarajit; Haldar, Atanu; Basu, Parthasarathi; Biswas, Jaydip; Baral, Rathindranath
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /04/2011 EN
Relevância na Pesquisa
45.77%
Myeloid-derived dendritic cells (DCs) generated from monocytes obtained from stage IIIB cervical cancer (CaCx IIIB) patients show dysfunctional maturation; thus, antitumor T cell functions are dysregulated. In an objective to optimize these dysregulated immune functions, the present study is focused on the ability of neem leaf glycoprotein (NLGP), a nontoxic preparation of the neem leaf, to induce optimum maturation of dendritic cells from CaCx IIIB patients. In vitro NLGP treatment of immature DCs (iDCs) obtained from CaCx IIIB patients results in upregulated expression of various cell surface markers (CD40, CD83, CD80, CD86, and HLA-ABC), which indicates DC maturation. Consequently, NLGP-matured DCs displayed balanced cytokine secretions, with type 1 bias and noteworthy functional properties. These DCs displayed substantial T cell allostimulatory capacity and promoted the generation of cytotoxic T lymphocytes (CTLs). Although NLGP-matured DCs derived from CaCx monocytes are generally subdued compared to those with a healthy monocyte origin, considerable revival of the suppressed DC-based immune functions is noted in vitro at a fairly advanced stage of CaCx, and thus, further exploration of ex vivo and in vivo DC-based vaccines is proposed. Moreover...

Kinase Suppressor of Ras (KSR1) modulates multiple Kit-ligand-dependent mast cell functions

Chen, Mia; Burgin, Sarah; Staser, Karl; He, Yongzheng; Li, Xiaohong; Robinson, Mikella; Jiang, Li; Chan, Rebecca J.; Ingram, David; Clapp, D. Wade
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
45.85%
The intricately regulated Ras pathway coordinates multiple kit-ligand induced mast cell functions, including chemotaxis, proliferation and degranulation. However, the intracellular proteins that modulate the intensity and duration of SCF-induced signals and the consequent cellular response are incompletely understood. Scaffolding proteins coordinate the spatial organization of MAPK proteins that may potentiate and/or inhibit cell functions. The Kinase Suppressor of Ras (KSR1) protein is known to function as a molecular scaffold and coordinates the organization of Raf/Mek/Erk in response to receptor tyrosine kinases. However, the impact of KSR1 in myeloid mast cell functions and in response to stem cell factor remains unknown. In the present study, we investigated the role of KSR1 in regulating cellular functions of bone marrow derived mast cells (BMMCs) of KSR1 deficient (−/−) mice. Genetic disruption of KSR1 resulted in both striking reductions in kit-ligand mediated proliferation and degranulation that are commonly attributed to MAPK signals. Surprisingly, disruption of the KSR1 scaffold also resulted in a decline in migration that is generally not linked to Raf-Erk signals. We found that loss of KSR1 does impact the biochemical activation of Pak kinase...

Tumor Secretion of VEGF Induces Endothelial Cells to Suppress T cell Functions Through the Production of PGE2

Mulligan, Jennifer K.; Rosenzweig, Steven A.; Young, M. Rita I.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em //2010 EN
Relevância na Pesquisa
45.88%
Endothelial cells are potent regulators of immune cell functions and have therefore been examined to determine their role in tumor-induced immune suppression. Previous studies by our laboratory showed that exposure to Lewis lung carcinoma (LLC)-secreted products induced endothelial cells to suppress T-cell functions in vitro. The current studies examined in vitro and in vivo the mechanism by which tumors induce the formation of suppressor endothelial cells and the means by which suppressor endothelial cells disrupt T-cell functions. In vitro studies demonstrated that inhibition of tumor-derived VEGF with neutralizing antibodies or treatment of endothelial cells with the VEGF receptor tyrosine kinase inhibitor, SU5416, prevented endothelial cells from being induced to suppress T-cell functions. Treatment of tumor-bearing mice with SU5416 blocked the development of endothelial cells that are suppressive to CD4+ and CD8+ T-cell functions. We next examined the role of suppressor endothelial cell-derived PGE2 in the inhibition of T-cell functions. Abrogation of endothelial cell PGE2 production in vitro with indomethacin prevented tumor-conditioned media from stimulating endothelial cell production of immune inhibitory activity toward T-cell functions. Similar treatment of endothelial cells from lungs of tumor-bearing mice blocked their capacity to produce T-cell-inhibitory mediators. These studies demonstrate that tumor-derived VEGF induces endothelial cells to upregulate production of PGE2 which...

Modulation of host natural killer cell functions in breast cancer via prostaglandin E2 receptors EP2 and EP4

Holt, Dawn; Ma, Xinrong; Kundu, Namita; Collin, Peter D; Fulton, Amy M
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em //2012 EN
Relevância na Pesquisa
45.8%
Breast malignancies often have high levels of COX-2. The COX-2 product prostaglandin E2 (PGE2) contributes to the high metastatic capacity of breast tumors. Our published data indicates that inhibiting either PGE2 production or PGE2-mediated signaling through the PGE2 receptor EP4 (one of four EP expressed on the malignant cell) reduces metastasis by a mechanism that requires Natural Killer (NK) cells. Tumor derived PGE2 and exogenous PGE2 are known to have direct inhibitory effects on NK cell functions, but less is known regarding which EP receptors mediate these effects. We now show that several NK functions (lysis, migration, cytokine production) are compromised in tumor-bearing mice and that tumor produced PGE2 interferes with NK cell functions. PGE2 inhibits the potential of NK cells to migrate, exert cytotoxic effects, and secrete IFNγ. The ability of PGE2 to inhibit NK cells from tumor bearing mice is by acting on EP2 and EP4 receptors. NK cells from tumor-bearing mice were more sensitive to inhibition by EP4 and EP2 agonists compared to endogenous NK cells from healthy mice. PGE2 was inhibitory to most NK functions of either normal or tumor-bearing mice. In contrast, there was a trend for enhanced TNFα production in response to PGE2 by NK cells from tumor-bearing mice. We also report that a recently described EP4 antagonist...

SAP modulates B cell functions in a genetic background-dependent manner

Detre, Cynthia; Yigit, Burcu; Keszei, Marton; Castro, Wilson; Magelky, Erica M.; Terhorst, Cox
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
45.79%
Mutations affecting the SLAM-associated protein (SAP) are responsible for the X-linked lympho-proliferative syndrome (XLP), a severe primary immunodeficiency syndrome with disease manifestations that include fatal mononucleosis, B cell lymphoma and dysgammaglobulinemia. It is well accepted that insufficient help by SAP−/− CD4+ T cells, in particular during the germinal center reaction, is a component of dysgammaglobulinemia in XLP patients and SAP−/− animals. It is however not well understood whether in XLP patients and SAP−/− mice B cell functions are affected, even though B cells themselves do not express SAP. Here we report that B cell intrinsic responses to haptenated protein antigens are impaired in SAP−/− mice and in Rag−/− mice into which B cells derived from SAP−/− mice together with wt CD4+ T cells had been transferred. This impaired B cells functions are in part depending on the genetic background of the SAP−/− mouse, which affects B cell homeostasis. Surprisingly, stimulation with an agonistic anti-CD40 causes strong in vivo and in vitro B cell responses in SAP−/− mice. Taken together, the data demonstrate that genetic factors play an important role in the SAP-related B cell functions. The finding that anti-CD40 can in part restore impaired B cell responses in SAP−/− mice...

Reprogramming the host: Modification of cell functions upon viral infection

Alvisi, Gualtiero; Palù, Giorgio
Fonte: Baishideng Publishing Group Co., Limited Publicador: Baishideng Publishing Group Co., Limited
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
45.75%
Viruses and their hosts have co-evolved for million years. In order to successfully replicate their genome, viruses need to usurp the biosynthetic machinery of the host cell. Depending on the complexity and the nature of the genome, replication might involve or not a relatively large subset of viral products, in addition to a number of host cell factors, and take place in several subcellular compartments, including the nucleus, the cytoplasm, as well as virus-induced, rearranged membranes. Therefore viruses need to ensure the correct subcellular localization of their effectors and to be capable of disguising from the cellular defensive mechanisms. In addition, viruses are capable of exploiting host cell activities, by modulating their post-translational modification apparatus, resulting in profound modifications in the function of cellular and viral products. Not surprisingly infection of host cells by these parasites can lead to alterations of cellular differentiation and growing properties, with important pathogenic consequences. In the present hot topic highlight entitled “Reprogramming the host: modification of cell functions upon viral infection”, a number of leading virologists and cell biologist thoroughly describe recent advances in our understanding of how viruses modulate cellular functions to achieve successful replication and propagation at the expenses of human cells.

KLRG1 Negatively Regulates Natural Killer Cell Functions through the Akt Pathway in Individuals with Chronic Hepatitis C Virus Infection

Wang, Jia M.; Cheng, Yong Q.; Shi, Lei; Ying, Ruo S.; Wu, Xiao Y.; Li, Guang Y.; Moorman, Jonathan P.; Yao, Zhi Q.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /11/2013 EN
Relevância na Pesquisa
45.73%
In this study, we demonstrate that killer cell lectin-like receptor subfamily G member 1 (KLRG1), a transmembrane protein preferentially expressed on T cells, is highly expressed on CD56+ NK cells, which are significantly reduced in their numbers and functions in the peripheral blood of patients with chronic hepatitis C virus (HCV) infection compared to subjects without infection. KLRG1 expression is also upregulated on healthy NK cells exposed to Huh-7 hepatocytes infected with HCV in vitro. Importantly, the expression levels of KLRG1 are inversely associated with the capacity of NK cells to proliferate and to produce gamma interferon (IFN-γ) but positively associated with apoptosis of NK cells in response to inflammatory cytokine stimulation. KLRG1+ NK cells, including CD56bright and CD56dim subsets, exhibit impaired cell activation and IFN-γ production but increased apoptosis compared to KLRG1− NK cells, particularly in HCV-infected individuals. Importantly, blockade of KLRG1 signaling significantly recovered the impaired IFN-γ production by NK cells from HCV-infected subjects. Blockade of KLRG1 also enhanced the impaired phosphorylation of Akt (Ser473) in NK cells from HCV-infected subjects. Taken together, these results indicate that KLRG1 negatively regulates NK cell numbers and functions via the Akt pathway...

Immunomodulation of Selective Naive T Cell Functions by p110δ Inactivation Improves the Outcome of Mismatched Cell Transplantation

Doisne, Jean-Marc; Hüber, Christian M.; Okkenhaug, Klaus; Colucci, Francesco
Fonte: Cell Press Publicador: Cell Press
Tipo: Artigo de Revista Científica
Publicado em 05/02/2015 EN
Relevância na Pesquisa
55.7%
Allogeneic hematopoietic stem cell transplantation (HSCT) can treat certain hematologic malignancies due to the graft versus leukemia (GvL) effect but is complicated by graft versus host disease (GvHD). Expression of the p110δ catalytic subunit of the phosphoinositide 3-kinase pathway is restricted to leukocytes, where it regulates proliferation, migration, and cytokine production. Here, in a mouse model of fully mismatched hematopoietic cell transplantation (HCT), we show that genetic inactivation of p110δ in T cells leads to milder GvHD, whereas GvL is preserved. Inactivation of p110δ in human lymphocytes reduced T cell allorecognition. We demonstrate that both allostimulation and granzyme B expression were dependent on p110δ in naive T cells, which are the main mediators of GvHD, whereas memory T cells were unaffected. Strikingly, p110δ is not mandatory for either naive or memory T cells to mediate GvL. Therefore, immunomodulation of selective naive T cell functions by p110δ inactivation improves the outcome of allogeneic HSCT.

Role of the protein tyrosine phosphatase DEP-1 in Src activation and the mediation of biological cell functions of endothelial and breast cancer cells

Spring, Kathleen
Fonte: Université de Montréal Publicador: Université de Montréal
Tipo: Thèse ou Mémoire numérique / Electronic Thesis or Dissertation
EN
Relevância na Pesquisa
45.81%
L’implication des protéines tyrosines phosphatases (PTPs) dans la régulation de la signalisation et la médiation des fonctions cellulaires a été bien établie dans les dernières années. Cependant, les mécanismes moléculaires par lesquels les PTPs régulent les processus fondamentaux tels que l’angiogenèse demeurent méconnus. Il a été rapporté que l’expression de la PTP DEP-1 (Density-enhanced phosphatase 1) augmente avec la densité cellulaire et corrèle avec la déphosphorylation du récepteur VEGFR2. Cette déphosphorylation contribue à l’inhibition de contact dans les cellules endothéliales à confluence et diminue l’activité du VEGFR2 en déphosphorylant spécifiquement ses résidus catalytiques Y1054/1059. De plus, la plupart des voies de signalisation en aval du VEGFR2 sont diminuées sauf la voie Src-Gab1-AKT. DEP-1 déphosphoryle la Y529 de Src et contribue à la promotion de la survie dans les cellules endothéliales. L’objectif de cette thèse est de mieux définir le rôle de DEP-1 dans la régulation de l’activité de Src et les réponses biologiques dans les cellules endothéliales. Nous avons identifié les résidus Y1311 et Y1320 dans la queue C-terminale de DEP-1 comme sites majeurs de phosphorylation en réponse au VEGF. La phosphorylation de ces résidus est requise pour l’activation de Src et médie le remodelage des jonctions cellules-cellules dépendantes de Src. Ce remodelage induit la perméabilité...

EVALUATION OF UNK CELL CAPACITY TO INITIATE PREGNANCY-ASSOCIATED SPIRAL ARTERY REMODELLING

BILINSKI, Michael
Fonte: Quens University Publicador: Quens University
Tipo: Tese de Doutorado
EN; EN
Relevância na Pesquisa
45.8%
Transient uterine Natural Killer (uNK) cells are the predominant leukocytes of early gestational human and murine uteri. Murine uNK cells promote changes in endometrial structure including initiation of perivascular smooth muscle reduction in spiral arteries. Less is known about human uNK cell functions due to sampling constraints. Xenogeneic engraftment of human lymphocyte progenitors to alymphoid mice has been useful in understanding human lymphocyte functions in vivo. Irradiation of recipients is required to create a niche for successful humanization of the mice but renders recipient mice sterile. The goal of my thesis was to develop a protocol enabling engraftment of human hematopoietic stem cells in alymphoid mice that would permit differentiation of functional human uNK cells. I then planned to evaluate human uNK cell functions and their regulation in vivo. Neonatal Rag2-/-Il2rg-/- mice, which lack T cells, B cells and NK cells were preconditioned with 5-fluorouracil and inoculated with syngeneic mouse bone marrow cells. As adults, inoculated female mice conceived and differentiated functional mouse uNK cells. In contrast, neonatally-preconditioned Rag2-/-Il2rg-/- mice inoculated with human cord blood hematopoietic stem cells conceived but differentiated non-lymphoid cells in sites normally occupied by uNK cells. Weekly injections of human IL-15...

Immunomodulation of selective na?ve T cell functions by p110? inactivation improves the outcome of allogeneic hematopoietic cell transplantation

Doisne, Jean-Marc; H?ber, Christian M.; Okkenhaug, Klaus; Colucci, Francesco
Fonte: Cell Press Publicador: Cell Press
Tipo: Article; published version
EN
Relevância na Pesquisa
55.71%
This is the final published version. It originally appeared in Cell Reports,10, 702?710 February 10, 2015, DOI: 10.1016/j.celrep.2015.01.002.; Allogeneic hematopoietic stem cell transplantation (HSCT) can treat certain hematologic malignancies due to the graft versus leukemia (GvL) effect but is complicated by graft versus host disease (GvHD). Expression of the p110? catalytic subunit of the phosphoinositide 3-kinase pathway is restricted to leukocytes, where it regulates proliferation, migration, and cytokine production. Here, in a mouse model of fully mismatched hematopoietic cell transplantation (HCT), we show that genetic inactivation of p110? in T cells leads to milder GvHD, whereas GvL is preserved. Inactivation of p110? in human lymphocytes reduced T cell allorecognition. We demonstrate that both allostimulation and granzyme B expression were dependent on p110? in naive T cells, which are the main mediators of GvHD, whereas memory T cells were unaffected. Strikingly, p110? is not mandatory for either naive or memory T cells to mediate GvL. Therefore, immunomodulation of selective naive T cell functions by p110? inactivation improves the outcome of allogeneic HSCT.; This work was supported by grants from Biotechnology and Biological Sciences Research Council...