Suchergebnisse

11 pages, 8 figures.-- PMID: 17998387 [PubMed].-- PMCID: PMC2118532.-- Printed version published Nov 26, 2007. ; Supporting information attached: Information on Western blots, Immunoprecipitation assays, the Rac activation assay, the FACS-based conjugate formation assay, the Actin polymerization assay, and Stimulation with antibody-coated beads and immunofluorescence.-- Also available at: http://jem.rupress.org/cgi/content/full/jem.20070366/DC1 ; Class I phosphoinositide 3–kinases (PI3Ks) constitute a family of enzymes that generates 3-phosphorylated polyphosphoinositides at the cell membrane after stimulation of protein tyrosine (Tyr) kinase–associated receptors or G protein–coupled receptors (GPCRs). The class I PI3Ks are divided into two types: class I(A) p85/p110 heterodimers, which are activated by Tyr kinases, and the class I(B) p110γ isoform, which is activated by GPCR. Although the T cell receptor (TCR) is a protein Tyr kinase–associated receptor, p110γ deletion affects TCR-induced T cell stimulation. We examined whether the TCR activates p110γ, as well as the consequences of interfering with p110γ expression or function for T cell activation. We found that after TCR ligation, p110γ interacts with Gα(q/11), lymphocyte-specific Tyr kinase, and ζ-associated protein. TCR stimulation activates p110γ which affects 3-phosphorylated polyphosphoinositide levels at the immunological synapse. We show that TCR-stimulated p110γ controls RAS-related C3 botulinum substrate 1 activity, F-actin polarization, and the interaction between T cells and antigen-presenting cells, illustrating a crucial role for p110γ in TCR-induced T cell activation. ; I. Alcázar holds a predoctoral fellowship from the Association for International Cancer Research, M. Marqués receives a predoctoral fellowship from the Spanish Ministry of Education and Science University Instructor Training Program, and D.F. Barber held a Ramón y Cajal contract from the Spanish Ministry of Education and Science and a Contract-in-Aid from the Fundación Científica de la Asociación Española Contra el Cancer. This work was supported by grants from the European Union (QLRT2001-02171), the Community of Madrid (8.3/0030/2000), the Ramón Areces Foundation (to D.F. Barber and A.C. Carrera), and the Spanish Dirección General de Ciencia y Desarrollo Tecnológico (SAF2004-00815 and SAF2004-05955- C02-01 to D.F. Barber A.C. Carrera, respectively). The Department of Immunology and Oncology was founded and is supported by the Spanish National Research Council (Consejo Superior de Investigaciones Científicas) and by Pfizer. ; Peer reviewed

T cells successfully fighting cancer
Else Marit Inderberg and Sébastien Wälchli from Oslo University Hospital explore what we need to know about T cells successfully fighting cancer. Cell-based immunotherapy uses the patient's own immune cells to target and kill cancer cells in a specific manner. Lymphocytes called T cells are mainly used for this type of therapy, and to target them more efficiently against cancer cells, they are genetically modified to express chimeric antigen receptors (CAR) or T cell receptors (TCR) that bind proteins or peptides presented on the surface of cancer cells. There are currently six CAR T cell therapies approved for the treatment of blood cancers. However, none of these cellular therapies are yet available outside clinical studies for solid cancers.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation in joints, associated with synovial hyperplasia and with bone and cartilage destruction. Although the primacy of T cell-related events early in the disease continues to be debated, there is strong evidence that autoantigen recognition by specific T cells is crucial to the pathophysiology of rheumatoid synovitis. In addition, T cells are key components of the immune cell infiltrate detected in the joints of RA patients. Initial analysis of the cytokines released into the synovial membrane showed an imbalance, with a predominance of proinflammatory mediators, indicating a deleterious effect of Th1 T cells. There is nonetheless evidence that Th17 cells also play an important role in RA. T cells migrate from the bloodstream to the synovial tissue via their interactions with the endothelial cells that line synovial postcapillary venules. At this stage, selectins, integrins, and chemokines have a central role in blood cell invasion of synovial tissue, and therefore in the intensity of the inflammatory response. In this review, we will focus on the mechanisms involved in T cell attraction to the joint, the proteins involved in their extravasation from blood vessels, and the signaling pathways activated. Knowledge of these processes will lead to a better understanding of the mechanism by which the systemic immune response causes local joint disorders and will help to provide a molecular basis for therapeutic strategies. ; This work was supported in part by grants from the Spanish Ministry of Science and Innovation (SAF 2011-27370 and SAF2014-53416R),the RETICS Program (RD12/0009/009;RIER), and the Madrid Regional Government (S2010/BMD-2350;RAPHYME). ; Peer reviewed

Bacterial phagocytosis and antigen cross-presentation to activate CD8+ T cells are principal functions of professional antigen presenting cells. However, conventional CD4+ T cells also capture and kill bacteria from infected dendritic cells in a process termed transphagocytosis (also known as transinfection). Here, we show that transphagocytic T cells present bacterial antigens to naive CD8+ T cells, which proliferate and become cytotoxic in response. CD4+ T-cell-mediated antigen presentation also occurs in vivo in the course of infection, and induces the generation of central memory CD8+ T cells with low PD-1 expression. Moreover, transphagocytic CD4+ T cells induce protective anti-tumour immune responses by priming CD8+ T cells, highlighting the potential of CD4+ T cells as a tool for cancer immunotherapy. ; J.M.G.-G. is supported by the Miguel Servet Program (Instituto de Salud Carlos III; ISCIII) and V.Z. by the ISCIII. This work was supported by grants from the Spanish Ministries of Science and Technology (MICINN; BFU2011-29450 to E.V.) and of Economy and Competitiveness (MINECO; SAF201456716-REDT and BFU2014-59585-R to E.V., SAF2014-55579-R to F.S.M., SAF201347975-R to B.A., SAF2014-58895-JIN to A.C.-A.), the ISCIII (PI14/00526; CP11/00145; CPII16/00022 to J.M.G.-G.), the Fundación Ramón Areces (to J.M.G.-G.), the Madrid regional government (INDISNET-S2011/BMD-2332 to F.S.M.) and the European Research Council (ERC-2011-AdG 294340-GENTRIS to F.S.M.; ERC 2013-AdG 334763 NOVARIPP to B.A.). F.S.M. and J.M.G.-G. are also financed by CIBER Cardiovascular, Spain. ; Sí

The biology and function of NKG2H receptor, unlike the better characterized members of the NKG2 family NKG2A, NKG2C, and NKG2D, remains largely unclear. Here, we show that NKG2H is able to associate with the signaling adapter molecules DAP12 and DAP10 suggesting that this receptor can signal for cell activation. Using a recently described NKG2H-specific monoclonal antibody (mAb), we have characterized the expression and function of lymphocytes that express this receptor. NKG2H is expressed at the cell surface of a small percentage of peripheral blood mononuclear cell (PBMC) and is found more frequently on T cells, rather than NK cells. Moreover, although NKG2H is likely to trigger activation, co-cross-linking of this receptor with an NKG2H-specific mAb led to decreased T cell activation and proliferation in polyclonal PBMC cultures stimulated by anti-CD3 mAbs. This negative regulatory activity was seen only after cross-linking with NKG2H, but not NKG2A- or NKG2C-specific monoclonal antibodies. The mechanism underlying this negative effect is as yet unclear, but did not depend on the release of soluble factors or recognition of MHC class I molecules. These observations raise the intriguing possibility that NKG2H may be a novel marker for T cells able to negatively regulate T cell responses. ; Work was supported by grants from the Fondo de Investigación Sanitaria (PI11/00298 and PI08/1701), MINECO (SAF2012-32293, SAF2015-69169-R, and SAF2014-58752-R), and the Regional Government of Madrid (grant S2010/BMD2326). DD was funded by an International predoctoral fellowship from La Caixa foundation.

Not Available ; The gills of fish are a mucosal tissue that contains T cells involved in the recognition of non-self and pathogens, and in this work we describe some features of gill-associated T cells of European sea bass, a marine model species. A whole transcriptome was obtained by deep sequencing of RNA from unstimulated gills that has been analyzed for the presence of T cell-related transcripts. Of the putative expressed sequences identified in the transcriptome, around 30 were related to main functions related to T cells including Th1/Th2/Th17/Treg cell subpopulations, thus suggesting their possible presence in the branchial epithelium. The number of T cells in the gills of sea bass, measured with the specific T cell mAb DLT15 range from 10% to 20%, and IHC analysis shows their abundance and distribution in the epithelium. Leukocytes from gills are able to proliferate in the presence of lectins ConA and PHA, as measured by flow cytometry using CFSE fluorescence incorporation, and during proliferation the number of T cells counted by immunofluorescence increased. In lectin-proliferating cells the expression of T cell-related genes TRβ, TRγ, CD4, CD8α, CD45 and IL-10 increased dramatically. Our data represent a first analysis on T cell genes and on basic T cell activities of fish gills, and suggest the presence of functionally active subpopulations of T lymphocytes in this tissue. ; The European Commission under the 7th Framework Programme for Research and Technological Development (FP7) of the European Union (Grant Agreement 311993 TARGETFISH).