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Pantaleo G.,University of Lausanne | Pantaleo G.,Swiss Vaccine Research Institute | Esteban M.,CSIC - National Center for Biotechnology | Jacobs B.,Arizona State University | Tartaglia J.,Sanofi S.A.
Current Opinion in HIV and AIDS | Year: 2010

Purpose of review: In this review, we will provide the scientific rationale for the use of poxvirus vectors in the field of HIV vaccines, the immunological profile of the vaccine-induced immune responses, an update on the current use of poxvirus vector-based vaccines in HIV vaccine clinical trials, and the development of new modified poxvirus vectors with improved immunological profile. Recent Findings: An Ad5-HIV vaccine was tested in a phase IIb clinical trial (known as the Step trial). Vaccinations in the Step trial were discontinued because the vaccine did not show any effect on acquisition of infection and on viral load. After the disappointing failure of the Step trial, the field of HIV vaccine has regained enthusiasm and vigour due to the promising protective effect observed in the phase III efficacy trial (known as RV-144) performed in Thailand which has tested a poxvirus-gp120 combination. Summary: The RV-144 phase III has provided for the first time evidence that an HIV vaccine can prevent HIV infection. The results from the RV-144 trial are providing the scientific rationale for the future development of the HIV vaccine field and for designing future efficacy trials. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Gerlach C.,Netherlands Cancer Institute | Van Heijst J.W.J.,Netherlands Cancer Institute | Swart E.,Netherlands Cancer Institute | Sie D.,Netherlands Cancer Institute | And 8 more authors.
Journal of Experimental Medicine | Year: 2010

The mechanism by which the immune system produces effector and memory T cells is largely unclear. To allow a large-scale assessment of the development of single naive T cells into different subsets, we have developed a technology that introduces unique genetic tags (barcodes) into naive T cells. By comparing the barcodes present in antigen-specific effector and memory T cell populations in systemic and local infection models, at different anatomical sites, and for TCR-pMHC interactions of different avidities, we demonstrate that under all conditions tested, individual naive T cells yield both effector and memory CD8+ T cell progeny. This indicates that effector and memory fate decisions are not determined by the nature of the priming antigen-presenting cell or the time of T cell priming. Instead, for both low and high avidity T cells, individual naive T cells have multiple fates and can differentiate into effector and memory T cell subsets. © 2010 Gerlach et al.

Wiede F.,Monash University | Ziegler A.,Monash University | Zehn D.,Swiss Vaccine Research Institute | Tiganis T.,Monash University
Journal of Autoimmunity | Year: 2014

Antigen cross-presentation by dendritic cells is crucial for priming cytotoxic CD8+ T cells to invading pathogens and tumour antigens, as well as mediating peripheral tolerance to self-antigens. The protein tyrosine phosphatase N2 (PTPN2) attenuates T cell receptor (TCR) signalling and tunes CD8+ T cell responses invivo. In this study we have examined the role of PTPN2 in the maintenance of peripheral tolerance after the cross-presentation of pancreatic β-cell antigens. The transfer of OVA-specific OT-I CD8+ T cells (C57BL/6) into RIP-mOVA recipients expressing OVA in pancreatic β-cells only results in islet destruction when OVA-specific CD4+ T cells are co-transferred. Herein we report that PTPN2-deficient OT-I CD8+ T cells transferred into RIP-mOVA recipients acquire CTL activity and result in β cell destruction and the development of diabetes in the absence of CD4+ help. These studies identify PTPN2 as a critical mediator of peripheral T cell tolerance limiting CD8+ T cell responses after the cross-presentation of self-antigens. Our findings reveal a mechanism by which PTPN2 SNPs might convert a tolerogenic CD8+ T cell response into one capable of causing the destruction of pancreatic β-cells. Moreover, our results provide insight into potential approaches for enhancing T cell-mediated immunity and/or T cell adoptive tumour immunotherapy. © 2014 Elsevier Ltd.

Harari A.,University of Lausanne | Harari A.,Swiss Vaccine Research Institute | Rozot V.,University of Lausanne | Enders F.B.,University of Lausanne | And 13 more authors.
Nature Medicine | Year: 2011

Rapid diagnosis of active Mycobacterium tuberculosis (Mtb) infection remains a clinical and laboratory challenge. We have analyzed the cytokine profile (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2)) of Mtb-specific T cells by polychromatic flow cytometry. We studied Mtb-specific CD4+ T cell responses in subjects with latent Mtb infection and active tuberculosis disease. The results showed substantial increase in the proportion of single-positive TNF-α Mtb-specific CD4+ T cells in subjects with active disease, and this parameter was the strongest predictor of diagnosis of active disease versus latent infection. We validated the use of this parameter in a cohort of 101 subjects with tuberculosis diagnosis unknown to the investigator. The sensitivity and specificity of the flow cytometry-based assay were 67% and 92%, respectively, the positive predictive value was 80% and the negative predictive value was 92.4%. Therefore, the proportion of single-positive TNF-α Mtb-specific CD4+ T cells is a new tool for the rapid diagnosis of active tuberculosis disease. © 2011 Nature America, Inc. All rights reserved.

King C.,University of Basel | Koehli S.,University of Basel | Hausmann B.,University of Basel | Schmaler M.,University of Basel | And 2 more authors.
Immunity | Year: 2012

The strength of interactions between T cell receptors and the peptide-major histocompatibility complex (pMHC) directly modulates T cell fitness, clonal expansion, and acquisition of effector properties. Here we show that asymmetric T cell division is an important mechanistic link between increased signal strength, effector differentiation, and the ability to induce tissue pathology. Recognition of pMHC above a threshold affinity drove responding T cells into asymmetric cell division. The ensuing proximal daughters underwent extensive division and differentiated into short-lived effector cells expressing the integrin VLA-4, allowing the activated T cell to infiltrate and mediate destruction of peripheral target tissues. In contrast, T cells activated by below-threshold antigens underwent symmetric division, leading to abortive clonal expansion and failure to fully differentiate into tissue-infiltrating effector cells. Antigen affinity and asymmetric division are important factors that regulate fate specification in CD8+ T cells and predict the potential of a self-reactive T cell to mediate tissue pathology. © 2012 Elsevier Inc.

Speiser D.E.,University of Lausanne | Utzschneider D.T.,Swiss Vaccine Research Institute | Utzschneider D.T.,University of Lausanne | Oberle S.G.,Swiss Vaccine Research Institute | And 5 more authors.
Nature Reviews Immunology | Year: 2014

Chronic viral infections and malignant tumours induce T cells that have a reduced ability to secrete effector cytokines and have upregulated expression of the inhibitory receptor PD1 (programmed cell death protein 1). These features have so far been considered to mark terminally differentiated 'exhausted' T cells. However, several recent clinical and experimental observations indicate that phenotypically exhausted T cells can still mediate a crucial level of pathogen or tumour control. In this Opinion article, we propose that the exhausted phenotype results from a differentiation process in which T cells stably adjust their effector capacity to the needs of chronic infection. We argue that this phenotype is optimized to cause minimal tissue damage while still mediating a critical level of pathogen control. In contrast to the presently held view of functional exhaustion, this new concept better reflects the pathophysiology and clinical manifestations of persisting infections, and it provides a rationale for emerging therapies that enhance T cell activity in chronic infection and cancer by blocking inhibitory receptors. © 2014 Macmillan Publishers Limited. All rights reserved.

Vigan S.,University of Lausanne | Perreau M.,University of Lausanne | Pantaleo G.,University of Lausanne | Pantaleo G.,Swiss Vaccine Research Institute | And 2 more authors.
Clinical and Developmental Immunology | Year: 2012

The immune system has evolved to allow robust responses against pathogens while avoiding autoimmunity. This is notably enabled by stimulatory and inhibitory signals which contribute to the regulation of immune responses. In the presence of a pathogen, a specific and effective immune response must be induced and this leads to antigen-specific T-cell proliferation, cytokines production, and induction of T-cell differentiation toward an effector phenotype. After clearance or control of the pathogen, the effector immune response must be terminated in order to avoid tissue damage and chronic inflammation and this process involves coinhibitory molecules. When the immune system fails to eliminate or control the pathogen, continuous stimulation of T cells prevents the full contraction and leads to the functional exhaustion of effector T cells. Several evidences both in vitro and in vivo suggest that this anergic state can be reverted by blocking the interactions between coinhibitory molecules and their ligands. The potential to revert exhausted or inactivated T-cell responses following selective blocking of their function made these markers interesting targets for therapeutic interventions in patients with persistent viral infections or cancer. Copyright © 2012 S. Vigan et al.

Koehli S.,University of Basel | Naeher D.,University of Basel | Galati-Fournier V.,University of Basel | Zehn D.,Swiss Vaccine Research Institute | And 2 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

T-cell receptor affinity for self-antigen has an important role in establishing self-tolerance. Three transgenic mouse strains expressing antigens of variable affinity for the OVA transgenic-I T-cell receptor were generated to address how TCR affinity affects the efficiency of negative selection, the ability to prime an autoimmune response, and the elimination of the relevant target cell. Mice expressing antigens with an affinity just above the negative selection threshold exhibited the highest risk of developing experimental autoimmune diabetes. The data demonstrate that close to the affinity threshold for negative selection, sufficient numbers of self-reactive T cells escape deletion and create an increased risk for the development of autoimmunity.

Herderschee J.,University of Lausanne | Fenwick C.,University of Lausanne | Pantaleo G.,University of Lausanne | Pantaleo G.,Swiss Vaccine Research Institute | And 2 more authors.
Journal of Leukocyte Biology | Year: 2015

During evolution, the immune system has diversified to protect the host from the extremely wide array of possible pathogens. Until recently, immune responses were dissected by use of global approaches and bulk tools, averaging responses across samples and potentially missing particular contributions of individual cells. This is a strongly limiting factor, considering that initial immune responses are likely to be triggered by a restricted number of cells at the vanguard of host defenses. The development of novel, single-cell technologies is a major innovation offering great promise for basic and translational immunology with the potential to overcome some of the limitations of traditional research tools, such as polychromatic flow cytometry or microscopy-based methods. At the transcriptional level, much progress has been made in the fields of microfluidics and single-cell RNA sequencing. At the protein level, mass cytometry already allows the analysis of twice as many parameters as flow cytometry. In this review, we explore the basis and outcome of immune-cell diversity, how genetically identical cells become functionally different, and the consequences for the exploration of host-immune defense responses. We will highlight the advantages, trade-offs, and potential pitfalls of emerging, single-cell-based technologies and how they provide unprecedented detail of immune responses. © Society for Leukocyte Biology.

Hebeisen M.,University of Lausanne | Oberle S.G.,Swiss Vaccine Research Institute | Oberle S.G.,University of Lausanne | Presotto D.,University of Lausanne | And 4 more authors.
Frontiers in Immunology | Year: 2013

Cytotoxic CD8 T cells mediate immunity to pathogens and they are able to eliminate malignant cells. Immunity to viruses and bacteria primarily involves CD8 T cells bearing high affinity T cell receptors (TCRs), which are specific to pathogen-derived (non-self) antigens. Given the thorough elimination of high affinity self/tumor-antigen reactive T cells by central and peripheral tolerance mechanisms, anti-cancer immunity mostly depends on TCRs with intermediate-to-low affinity for self-antigens. Because of this, a promising novel therapeutic approach to increase the efficacy of tumor-reactive T cells is to engineer their TCRs, with the aim to enhance their binding kinetics to pMHC complexes, or to directly manipulate the TCR-signaling cascades. Such manipulations require a detailed knowledge on how pMHC-TCR and co-receptors binding kinetics impact the T cell response. In this review, we present the current knowledge in this field. We discuss future challenges in identifying and targeting the molecular mechanisms to enhance the function of natural or TCR-affinity optimized T cells, and we provide perspectives for the development of protective anti-tumor T cell responses. © 2013 Hebeisen, Oberle, Presotto, Speiser, Zehn and Rufer.

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