100,415 research outputs found
Antigen-activated human T lymphocytes express cell-surface NKG2D ligands via an ATM/ATR-dependent mechanism and become susceptible to autologous NK-cell lysis
No full textRecent evidence indicates that natural killer (NK) cells can negatively regulate T-cell responses, but the mechanisms behind this phenomenon as a consequence of NK-T-cell interactions are poorly understood. We studied the interaction between the NKG2D receptor and its ligands (NKG2DLs), and asked whether T cells expressed NKG2DLs in response to superantigen, alloantigen, or a specific antigenic peptide, and if this rendered them susceptible to NK lysis. As evaluated by FACS, the major histocompatibility complex (MHC) class I chain-related protein A (MICA) was the ligand expressed earlier on both CD4(+) and CD8(+) T cells in 90% of the donors tested, while UL16-binding protein-1 (ULBP)1, ULBP2, and ULBP3 were induced at later times in 55%-75% of the donors. By carboxyfluorescein diacetate succinimidyl ester (CFSE) labeling, we observed that NKG2DLs were expressed mainly on T cells that had gone through at least one division. Real-time reverse-transcription polymerase chain reaction confirmed the expression of all NKG2DLs, except ULBP4. In addition, T-cell activation stimulated phosphorylation of ataxia-telangiectasia mutated (ATM), a kinase required for NKG2DLs expression after DNA damage, and ATM/Rad3-related kinase (ATR) inhibitors blocked MICA induction on T cells with a mechanism involving NF-kappaB. Finally, we demonstrated that activated T cells became susceptible to autologous NK lysis via NKG2D/NKG2DLs interaction and granule exocytosis, suggesting that NK lysis of T lymphocytes via NKG2D may be an additional mechanism to limit T-cell responses
Detuning CD8+ T lymphocytes by down-regulation of the activating receptor NKG2D: role of NKG2D ligands released by activated T cells.
No full textNKG2D is an activating receptor expressed on CD8(+)alpha beta(+) T cells, alpha beta(+) T cells, natural killer (NK) cells, and some CD4(+) T cells. For a long time, the interaction of NKG2D with its ligands (NKG2DLs) MICA, MICB, and ULBP1-3 has been considered a mechanism for recognition and elimination of tumor, infected, or otherwise "stressed" cells. However, a new role for NKG2D as an immunoregulatory receptor is emerging. Here, we show that NKG2D is strongly down-modulated on antigen-activated CD8(+) T cells but only if CD4(+) T cells are present. Down-modulation was caused by soluble factors produced by CD4(+) T cells, and in particular soluble NKG2DLs were found in the supernatants of antigen-activated T-cell cultures. MICB was the ligand released at higher levels when CD4(+) T cells were present in the cell cultures, suggesting that it could be the major player of NKG2D down-modulation. CD8(+) T cells expressing low levels of NKG2D had impaired effector functions, as evaluated by proliferation, cytokine production, and cytotoxicity assays after combined triggering of NKG2D and TCR-CD3 complex. These findings show that activated CD4(+) T cells expressing NKG2DLs can efficiently prevent NKG2D-mediated CD8(+) T-cell functions, and suggest that the NKG2D/NKG2DL interaction can regulate immune responses. (Blood. 2009; 113: 2955-2964
DNAM-1 ligand expression on Ag-stimulated T lymphocytes is mediated by ROS-dependent activation of DNA-damage response: relevance for NK-T cell interaction
No full textAn important role for natural killer (NK) cells in the regulation of T-cell responses is emerging, although the receptor pairs regulating the NK-T-cell interaction have still not been identified. We found that superantigen-stimulated T cells express Nectin-2 (CD112) and poliovirus receptor (PVR; CD155), the ligands of the activating NK receptor DNAX accessory molecule-1 (DNAM-1; CD226). Interestingly, only PVR was present at the T cell surface, particularly on cells in the S and G(2)/M phases of the cell cycle. The up-regulation of PVR expression involves DNA-damage response (DDR)-dependent pathways, because we found that pharmacologic inhibition of ATM and ATR kinases reduced PVR expression and that PVR was almost exclusively induced on cells expressing the DDR marker gamma H2AX. Oxidative stress contributed to DDR activation, and our results showed impaired PVR levels in the presence of the reactive oxygen species (ROS) scavenger N-acetyl-cysteine (NAC), being monocytes the main ROS source needed for optimal PVR expression on activated T cells. Interestingly, in accordance with ligand expression, NK cells lysed allogeneic proliferating more efficiently than nonproliferating T lymphocytes, with a mechanism requiring the cooperation between DNAM-1 and NKG2D. These results could contribute to unraveling the role of NK cells in the down-regulation of T-cell responses in physiologic and pathologic processes such as autoimmunity or GVHD. (Blood. 2011; 117(18): 4778-4786
Modulation of T Cell-Mediated Immune Responses by Natural Killer Cells
No full textNatural Killer (NK) cells are lymphoid cells that participate in innate immunity and in early defense against infections and tumors. NK cells express cell surface activating and inhibitory receptors that allow them to recognize and kill infected or tumor cells and rapidly produce cytokines and chemokines. Increasing evidence asserts an important immunomodulatory role of NK cells. We will discuss different mechanisms used by NK cells to regulate T cell-mediated immune responses
Semantic Enrichment of Scientific Documents with Semantic Lenses – Developing methodologies, tools and prototypes for their concrete use
No full textCon questa dissertazione di tesi miro ad illustrare i risultati della mia ricerca nel campo del Semantic Publishing, consistenti nello sviluppo di un insieme di metodologie, strumenti e prototipi, uniti allo studio di un caso d‟uso concreto, finalizzati all‟applicazione ed alla focalizzazione di Lenti Semantiche (Semantic Lenses)
NK cell regulation of T cell-mediated responses
No full textNK cells promote adaptive immune responses through their production of type I and type 2 cytokines or chemokines. Secretion of these factors by activated NK cells influences the differentiation of B and T lymphocytes. Increasing evidence indicates that NK cells are also directly involved in dendritic cell (DC) maturation. By contrast, a potential role for direct cell-cell interactions between NK and T lymphocytes, in particular CD4(+) T cells, has not been explored. We provide evidence that activated human NK cells are able of promoting TcR-dependent proliferation of resting autologous peripheral blood CD4(+) T cells by a process that involves costimulatory molecules of the immunoglobulin (Ig) and tumor necrosis factor (TNF) superfamilies. These findings suggest a novel link between natural and adaptative immune responses. (C) 2004 Elsevier Ltd. All rights reserved
Modulation of NKG2D expression in human CD8(+) T cells corresponding with tuberculosis drug cure.
No full textBACKGROUND: Biomarkers predicting tuberculosis treatment response and cure would facilitate drug development. This study investigated expression patterns of the co-stimulation molecule NKG2D in human tuberculosis and treatment to determine its potential usefulness as a host biomarker of tuberculosis drug efficacy. METHODS: Tuberculosis patients (n = 26) were recruited in Lahore, Pakistan, at diagnosis and followed up during treatment. Household contacts (n = 24) were also recruited. NKG2D expression was measured by qRT-PCR in RNA samples both ex vivo and following overnight mycobacterial stimulation in vitro. Protein expression of NKG2D and granzyme B was measured by flow cytometry. RESULTS: NKG2D expression in newly diagnosed tuberculosis patients was similar to household contacts in ex vivo RNA, but was higher following in vitro stimulation. The NKG2D expression was dramatically reduced by intensive phase chemotherapy, in both ex vivo blood RNA and CD8(+) T cell protein expression, but then reverted to higher levels after the continuation phase in successfully treated patients. CONCLUSION: The changes in NKG2D expression through successful treatment reflect modulation of the peripheral cytotoxic T cell response. This likely reflects firstly in vivo stimulation by live Mycobacterium tuberculosis, followed by the response to dead bacilli, antigen-release and finally immunopathology resolution. Such changes in host peripheral gene expression, alongside clinical and microbiological indices, could be developed into a biosignature of tuberculosis drug-induced cure to be used in future clinical trials
Effectiveness of extracorporeal photochemotherapy in the treatment of a case of refractory erosive lichen planus
No full textErosive lichen planus is characterized by painful, multi-focal erythematous-ulcerative areas affecting mucosal oral and genital areas. Topical therapies are usually ineffective, whereas systemic steroids and immunosuppressive agents are frequently associated with a wide spectrum of side effects. Herein, we presented our positive experience in the treatment of a case of multi-resistant erosive lichen planus with extracorporeal photochemotherapy
Reinforced glass: Structural potential of cast glass beams with embedded metal reinforcement
No full textThe shaping freedom of cast glass in combination with the robustness of the resulting voluminous components opens up new, exciting directions in the field of structural glass. Yet, cast glass components remain brittle, limiting their structural applications in hyper-static compressive structures designed with conservative safety factors. Stretching these limits, this work investigates the reinforcement of cast glass by incorporating metal bars during the casting process, in a similar principle to reinforced concrete. Aim is to increase the ductility of the composite glass component, provide a warning mechanism prior to ultimate fracture and secure a postfailure load-bearing capacity. The development of hybrid glass components involves kiln-casting experiments using different metal-glass combinations, of similar thermal expansion coefficients. The method of introducing the metal bar in the glass during casting, and the effect of the selected forming temperature are investigated. The resulting metal-glass interfaces are examined for micro-cracks using a digital microscope, and for internal stresses using cross-polarized light. Two material combinations are found successful; soda lime silica with titanium and alkali borosilicate with Kovar. A hybrid borosilicate-Kovar 30*30*240mm beam is further tested in 4-point bending until failure, while its displacement is measured by Digital Image Correlation. The flexural response of the composite component is compared to the performance of unreinforced cast glass beams of similar composition. Although reinforced and unreinforced specimens show a comparable flexural strength, the reinforced specimen exhibits a warning mechanism well before failure, a gradual fracture and a post-failure load-bearing capacity. These attributes encourage the further exploration of cast glass reinforcement.Green Open Access added to TU Delft Institutional Repository 'You share, we take care!' - Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Structural Design & MechanicsApplied Mechanic
- …
