Human CD81 directly enhances T(h)1 and T(h)2 cell activation, but preferentially induces proliferation of T(h)2 cells upon long-term stimulation

BACKGROUND: CD81, a cell-surface protein of the tetraspanin superfamily, has been shown to costimulate T cell activation in murine T cells, and is involved in development of Th2 immune responses in mice. RESULTS: Here it is shown that stimulation of CD81 on human T cells can enhance T cell activation by antigen or superantigen, causing an increase in the early activation marker CD69, and increasing the number of cytokine-producing and proliferating T cells. Interestingly, CD81 costimulates cytokine production by T cells producing both Th1 and Th2 cytokines. Although human CD81 is highly expressed on non-T as well as T cells, CD81 costimulation appears to act directly on T cells. Pre-incubation of purified T cells with anti-CD81 antibody is sufficient to increase T cell activation, while pre-incubation of non-T cells is not. However, long-term polyclonal stimulation of T cells by anti-CD3 antibody, in the presence of CD81 costimulation, biases T cells towards the production of IL-4 and not IFNγ. This is accomplished by a preferential proliferation of IL-4-producing cells. CONCLUSION: Thus, signalling through CD81 on T cells costimulates both Th1 and Th2 cells, but increases the number of Th2 cells during long-term activation

Nichtdermatomgebundene somatosensorische Defizite bei chronischen Schmerzpatienten

Zusammenfassung: Nichtdermatomgebundene somatosensorische Defizite (NDSD) sind bei chronischen Schmerzpatienten häufig und weisen auf Schmerzsensibilisierung und Schmerzzentralisierung hin. Klinisch findet sich in der Regel eine Berührungs- und Thermhypästhesie mit oftmals quadrantenartiger oder halbseitiger Ausbreitung. Bei der Mehrzahl der Patienten liegt anamnestisch ein somatisch-nozizeptives Auslöseereignis vor, das aber wie das komplexe regionale Schmerzsyndrom (CRPS) in keiner eindeutigen Relation zur nachfolgenden Schmerzstörung steht. Wie bei vielen chronischen Schmerzstörungen weisen auch Patienten mit NDSD oft eine überdurchschnittliche psychobiografische Stressbelastung auf. Die Ergebnisse der funktionellen Bildgebung weisen auf ein komplexes Muster zentralnervöser Dysregulationen hi

Exploring Multi-Agent Systems for Intermodal Freight Fleets: Literature-based Justification of a New Concept

Freight transportation is increasingly connected with the automation of fleet assets by intelligent systems. This study emerges from the consortium research project Gaia-X 4 ROMS, which aims to develop a comprehensive approach for smart freight fleets in the field of parcel deliveries. Within this project, a novel type of multi-agent system (MAS) applied to freight fleet management is being developed. To determine the state of prior research and recent developments in this field, a systematic literature review was conducted and presented herein. The findings of the review demonstrate a significant lack of applied solutions in this topic, highlighting the need for a novel approach. Accordingly, a first framework for the envisioned multi-agent system, as conceptualized within the consortium research project, is presented in this work, serving as a basis for subsequent design phases

Sharing is Caring:Multiprocessor Scheduling with a Sharable Resource

We consider a scheduling problem onm identical processors sharing an arbitrarily divisible resource. In addition to assigning jobs to processors, the scheduler must distribute the resource among the processors (e.g., for three processors in shares of 20%, 15%, and 65%) and adjust this distribution over time. Each job j comes with a size pj ∈R and a resource requirement rj >0. Jobs do not benefit when receiving a share larger than rj of the resource. But providing them with a fraction of the resource requirement causes a linear decrease in the processing efficiency. We seek a (non-preemptive) job and resource assignment minimizing the makespan. Our main result is an efficient approximation algorithm which achieves an approximation ratio of 2+1/(m−2). It can be improved to an (asymptotic) ratio of 1+1/(m−1) if all jobs have unit size. Our algorithms also imply new results for a well-known bin packing problem with splittable items and a restricted number of allowed item parts per bin. Based upon the above solution, we also derive an approximation algorithm with similar guarantees for a setting in which we introduce so-called tasks each containing several jobs and where we are interested in the average completion time of tasks (a task is completed when all its jobs are completed)

Harmonization of the intracellular cytokine staining assay

Active immunotherapy for cancer is an accepted treatment modality aiming to reinforce the T-cell response to cancer. T-cell reactivity is measured by various assays and used to guide the clinical development of immunotherapeutics. However, data obtained across different institutions may vary substantially making comparative conclusions difficult. The Cancer Immunotherapy Immunoguiding Program organizes proficiency panels to identify key parameters influencing the outcome of commonly used T-cell assays followed by harmonization. Our successes with IFNγ-ELISPOT and peptide HLA multimer analysis have led to the current study on intracellular cytokine staining (ICS). We report the results of three successive panels evaluating this assay. At the beginning, 3 out of 9 participants (33 %) were able to detect >6 out of 8 known virus-specific T-cell responses in peripheral blood of healthy individuals. This increased to 50 % of the laboratories in the second phase. The reported percentages of cytokine-producing T cells by the different laboratories were highly variable with coefficients of variation well over 60 %. Variability could partially be explained by protocol-related differences in background cytokine production leading to sub-optimal signal-to-noise ratios. The large number of protocol variables prohibited identification of prime guidelines to harmonize the assays. In addition, the gating strategy used to identify reactive T cells had a major impact on assay outcome. Subsequent harmonization of the gating strategy considerably reduced the variability within the group of participants. In conclusion, we propose that first basic guidelines should be applied for gating in ICS experiments before harmonizing assay protocol variables

Risk Factors and Prognosis in T-Cell Posttransplantation Lymphoproliferative Diseases: Reevaluation of 163 Cases

Background. Posttransplantation lymphoproliferative diseases (PTLD) are mainly Epstein-Barr virus (EBV)-associated disorders of B-cell origin. Due to the rarity of monomorphic T-cell PTLD (T-PTLD), knowledge about pathogenesis, risk factors, therapy, and prognosis relies predominantly on case reports and small series. Therefore, we aimed to provide an overview and a retrospective analysis of this rare PTLD subtype. Methods. We analyzed all available articles on T-PTLD in the PubMed database as well as in our own databases (Institute of Pathology/Department of Paediatric Haematology and Oncology, Hannover Medical School) from 1988 to 2010. Reevaluated parameters were gender, age, transplanted organ, immunosuppressant regimen, time between transplantation and T-PTLD manifestation, T-PTLD subtype, virus positivity, localization, therapy, and follow-up. Results. A total of 163 cases were evaluated. We found that hematopoietic stem cell transplantation was associated with early-onset T-PTLD, whereas late onset occurred after immunosuppression with steroids and azathioprine without administration of calcineurin inhibitors. The major independent favorable prognostic factors were T-PTLD of the large granular lymphocytic leukemia subtype, young age, and a combination of radiotherapy/radiochemotherapy and reduced immunosuppression, whereas the hepatosplenic T-cell lymphoma subtype and cases with involvement of bone marrow, the central nervous system, or graft had an adverse prognosis. Conclusion. T-PTLD is a heterogeneous group of different aberrant T-cell proliferations and represents a significant complication following transplantation, showing a uniformly poor prognosis

Letters to the Editor: Correspondence re R. Lapointe et al., CD40-stimulated B Lymphocytes Pulsed with Tumor Antigens Are Effective Antigen-presenting Cells That Can Generate Specific T Cells. Cancer Res 2003;63:2836–43.

La réplique provient de Réjean Lapointe, Jacques Thibodeau et Patrick Hwu; Réjean Lapointe et Jacques Thibodeau sont affiliés à la faculté de médecine de l'Université de Montréa

Comprehensive Immune Monitoring of Clinical Trials to Advance Human Immunotherapy.

The success of immunotherapy has led to a myriad of clinical trials accompanied by efforts to gain mechanistic insight and identify predictive signatures for personalization. However, many immune monitoring technologies face investigator bias, missing unanticipated cellular responses in limited clinical material. We present here a mass cytometry (CyTOF) workflow for standardized, systems-level biomarker discovery in immunotherapy trials. To broadly enumerate immune cell identity and activity, we established and extensively assessed a reference panel of 33 antibodies to cover major cell subsets, simultaneously quantifying activation and immune checkpoint molecules in a single assay. This assay enumerates ≥98% of peripheral immune cells with ≥4 positively identifying antigens. Robustness and reproducibility are demonstrated on multiple samples types, across two research centers and by orthogonal measurements. Using automated analysis, we identify stratifying immune signatures in bone marrow transplantation-associated graft-versus-host disease. Together, this validated workflow ensures comprehensive immunophenotypic analysis and data comparability and will accelerate biomarker discovery

Heat shock protein 70/peptide complexes: potent mediators for the generation of antiviral T cells particularly with regard to low precursor frequencies

<p>Abstract</p> <p>Background</p> <p>Heat shock protein 70 (HSP70) has gained major attention as an adjuvant capable of inducing antigen-specific CD8⁺and CD4⁺T-cell responses. The ability of HSP70/peptide complexes to elicit cytotoxic T-cell (CTL) responses by cross-presentation of exogenous antigens via HLA class I molecules is of central interest in immunotherapy. We examined the role of HSP70/CMVpp65_495-503-peptide complex (HSP70/CMV-PC) in HLA class I-restricted cross-presentation for <it>ex vivo </it>expansion of CMV-specific CTLs.</p> <p>Methods</p> <p>CMV-specific T cells generated from PBMCs of HLA-A*02:01/CMV-seropositive donors were stimulated for 21 days with HSP70/CMV-PC and analyzed in functional assays. As a control PBMCs were cultured in the presence of CMVpp65_495-503peptide or HSP70. Increase of CMV-specific CTLs was visualized by pentameric HLA-A*02:01/CMVpp65_495-503complex.</p> <p>Results</p> <p>About 90% of HSP70/CMV-PC generated T cells were CMV-specific and exhibited significantly higher IFN-γ secretion, cytotoxic activity, and an increased heme oxygenase 1 (HO-1) gene expression as compared to about 69% of those stimulated with CMVpp65_495-503peptide. We decided to classify the HLA-A*02:01/CMV-seropositive donors as weak, medium, and strong responder according to the frequency of generated A2/CMV-pentamer-positive CD8⁺T cells. HSP70/CMV-PC significantly induces strong antiviral T-cell responses especially in those donors with low memory precursor frequencies. Blockage of CD91 with α2-macroglobulin markedly reduced proliferation of antiviral T cells suggesting a major role of this receptor in the uptake of HSP70/CMV-PC.</p> <p>Conclusion</p> <p>This study clearly demonstrates that HSP70/CMV-PC is a potent mediator to induce stronger T-cell responses compared to antiviral peptides. This simple and efficient technique may help to generate significant quantities of antiviral CTLs by cross-presentation. Thus, we propose HSP70 for chaperoning peptides to reach an efficient level of cross-presentation. HSP70/peptide complexes may be particularly useful to generate stronger T-cell responses in cases of low precursor frequencies and may help to improve the efficiency of antigen-specific T-cell therapy for minor antigens.</p