Bernhard Moser

Cardiff University, Cardiff, Wales, United Kingdom

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Publications (114)930.8 Total impact

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    ABSTRACT: Unconventional T cells are gaining center stage as important effector and regulatory cells that orchestrate innate and adaptive immune responses. Human Vγ9/Vδ2 T cells are amongst the best understood unconventional T cells, as they are easily accessible in peripheral blood, can readily be expanded and manipulated in vitro, respond to microbial infections in vivo and can be exploited for novel tumor immunotherapies. We here review findings that suggest that Vγ9/Vδ2 T cells, and possibly other unconventional human T cells, play an important role in bridging innate and adaptive immunity by promoting the activation and differentiation of various types of antigen-presenting cells (APCs) and even turning into APCs themselves, and thereby pave the way for antigen-specific effector responses and long-term immunological memory. Although the direct physiological relevance for most of these mechanisms still needs to be demonstrated in vivo, these findings may have implications for novel therapies, diagnostic tests and vaccines. Copyright © 2015. Published by Elsevier Inc.
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    ABSTRACT: IMMUNOTHERAPY IS A FAST ADVANCING METHODOLOGY INVOLVING ONE OF TWO APPROACHES: (1) compounds targeting immune checkpoints and (2) cellular immunomodulators. The latter approach is still largely experimental and features in vitro generated, live immune effector cells, or antigen-presenting cells. γδ T cells are known for their efficient in vitro tumor killing activities. Consequently, many laboratories worldwide are currently testing the tumor killing function of γδ T cells in clinical trials. Reported benefits are modest; however, these studies have demonstrated that large γδ T-cell infusions were well tolerated. Here, we discuss the potential of using human γδ T cells not as effector cells but as a novel cellular vaccine for treatment of cancer patients. Antigen-presenting γδ T cells do not require to home to tumor tissues but, instead, need to interact with endogenous, tumor-specific αβ T cells in secondary lymphoid tissues. Newly mobilized effector αβ T cells are then thought to overcome the immune blockade by creating proinflammatory conditions fit for effector T-cell homing to and killing of tumor cells. Immunotherapy may include tumor antigen-loaded γδ T cells alone or in combination with immune checkpoint inhibitors.
    Frontiers in Immunology 10/2014; 5:512. DOI:10.3389/fimmu.2014.00512
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    ABSTRACT: The early immune response to microbes is dominated by the recruitment of neutrophils whose primary function is to clear invading pathogens. However, there is emerging evidence that neutrophils play additional effector and regulatory roles. The present study demonstrates that human neutrophils assume Ag cross-presenting functions and suggests a plausible scenario for the local generation of APC-like neutrophils through the mobilization of unconventional T cells in response to microbial metabolites. Vγ9/Vδ2 T cells and mucosal-associated invariant T cells are abundant in blood, inflamed tissues, and mucosal barriers. In this study, both human cell types responded rapidly to neutrophils after phagocytosis of Gram-positive and Gram-negative bacteria producing the corresponding ligands, and in turn mediated the differentiation of neutrophils into APCs for both CD4(+) and CD8(+) T cells through secretion of GM-CSF, IFN-γ, and TNF-α. In patients with acute sepsis, circulating neutrophils displayed a similar APC-like phenotype and readily processed soluble proteins for cross-presentation of antigenic peptides to CD8(+) T cells, at a time when peripheral Vγ9/Vδ2 T cells were highly activated. Our findings indicate that unconventional T cells represent key controllers of neutrophil-driven innate and adaptive responses to a broad range of pathogens.
    The Journal of Immunology 08/2014; 193(7). DOI:10.4049/jimmunol.1401018 · 5.36 Impact Factor
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    ABSTRACT: Cell-based immunotherapy strategies target tumors directly (via cytolytic effector cells) or aim at mobilizing endogenous anti-tumor immunity. The latter approach includes dendritic cells (DC), most frequently in the form of in vitro cultured peripheral blood monocytes-derived DC. Human blood γδT cells are selective for a single class of non-peptide agonists (“phosphoantigens”) and develop into potent antigen-presenting cells (APC), termed γδT-APC, within 1-3 days of in vitro culture. Availability of large numbers of γδT-APC would be advantageous for use as a novel cellular vaccine. We here report optimal γδT cell expansion (>107 cells/ml blood) when peripheral blood mononuclear cells (PBMC) from healthy individuals and melanoma patients were stimulated with zoledronate and then cultured for 14 days in the presence of IL-2 and IL-15, yielding γδT cell cultures of variable purity (77±21% and 56±26%, respectively). They resembled effector-memory αβT (TEM) cells and retained full functionality as assessed by in vitro tumor cell killing as well as secretion of proinflammatory cytokines (IFNγ, TNFα) and cell proliferation in response to stimulation with phosphoantigens. Importantly, day 14 γδT cells expressed numerous APC-related cell surface markers and, in agreement, displayed potent in vitro APC functions. Day 14 γδT cells from PBMC of patients with cancer were equally effective as their counterparts derived from blood of healthy individuals and triggered potent CD8+ αβT cell responses following processing and cross-presentation of simple (influenza M1) and complex (tuberculin purified protein derivative) protein antigens. Of note, and in clear contrast to peripheral blood γδT cells, the ability of day 14 γδT cells to trigger antigen-specific αβT cell responses did not depend on re-stimulation. We conclude that day 14 γδT cell cultures provide a convenient source of autologous APC for use in immunotherapy of patients with various cancers.
    Frontiers in Immunology 07/2014; doi: 10.3389/fimmu.2014.00344. DOI:10.3389/fimmu.2014.00344/abstract
  • 6th International Gamma Delta T cell Conference, University of Illinois Chicago, USA.; 05/2014
  • 6th International Gamma Delta T cell Conference, University of Illinois Chicago, USA.; 05/2014
  • British Society of Gene and Cell Therapy Conference, Institute of Child Health, University College London, London, United Kingdom,; 03/2014
  • MITReG Annual Symposium, Liberty Stadium Swansea, Wales, United Kingdom; 12/2013
  • Center for Integration of Medicine and Innovative Technology Conference, Krakow, Poland.; 04/2013
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    ABSTRACT: Aminobisphosphonates (NBPs) are used widely against excessive bone resorption in osteoporosis and Paget's disease as well as in metastatic bone disease and multiple myeloma. Intravenous NBP administration often causes mild to severe acute phase responses (APRs) that may require intervention with analgesics and antipyretics and lead to treatment non-compliance and non-adherence. We here undertook a phase IV safety trial in patients with osteoporosis to investigate the APR of otherwise healthy individuals to first-time intravenous treatment with the NBP zoledronate. This study provides unique insight into sterile acute inflammatory responses in vivo, in the absence of confounding factors such as infection or cancer. Our data show that both peripheral γδ T cells and monocytes become rapidly activated after treatment with zoledronate, which ultimately determines the clinical severity of the APR. Our study highlights a key role for IFN-γ in the zoledronate-induced APR and identifies pre-treatment levels of monocytes and central/memory Vγ9/Vδ2 T cells as well as their responsiveness to zoledronate in vitro as predictive risk factors for the occurrence of subclinical and clinical symptoms. These findings have diagnostic and prognostic implications for patients with and without malignancy and are relevant for Vγ9/Vδ2 T-cell based immunotherapy approaches. © 2012 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 03/2013; 28(3). DOI:10.1002/jbmr.1797 · 6.04 Impact Factor
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    ABSTRACT: Background Human γδ T cells reactive to the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP) contribute to acute inflammatory responses. We have previously shown that peritoneal dialysis (PD)-associated infections with HMB-PP producing bacteria are characterized by locally elevated γδ T-cell frequencies and poorer clinical outcome compared with HMB-PP negative infections, implying that γδ T cells may be of diagnostic, prognostic and therapeutic value in acute disease. The regulation by local tissue cells of these potentially detrimental γδ T-cell responses remains to be investigated.Methods Freshly isolated γδ or αβ T cells were cultured with primary mesothelial cells derived from omental tissue, or with mesothelial cell-conditioned medium. Stimulation of cytokine production and proliferation by peripheral T cells in response to HMB-PP or CD3/CD28 beads was assessed by flow cytometry.ResultsResting mesothelial cells were potent suppressors of pro-inflammatory γδ T cells as well as CD4(+) and CD8(+) αβ T cells. The suppression of γδ T-cell responses was mediated through soluble factors released by primary mesothelial cells and could be counteracted by SB-431542, a selective inhibitor of TGF-β and activin signalling. Recombinant TGF-β1 but not activin-A mimicked the mesothelial cell-mediated suppression of γδ T-cell responses to HMB-PP.Conclusions The present findings indicate an important regulatory function of mesothelial cells in the peritoneal cavity by dampening pro-inflammatory T-cell responses, which may help preserve the tissue integrity of the peritoneal membrane in the steady state and possibly during the resolution of acute inflammation.
    Nephrology Dialysis Transplantation 01/2013; 28(7). DOI:10.1093/ndt/gfs612 · 3.37 Impact Factor
  • Bernhard Moser
    Blood 12/2012; 120(26):5093-4. DOI:10.1182/blood-2012-10-460378 · 9.78 Impact Factor
  • 3rd International Conference on Stem Cells and Cancer: Proliferation, Differentiation, and Apoptosis, Dr. RML Hospital, New Delhi, India; 10/2012
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    ABSTRACT: The localization of memory T cells to human skin is essential for long-term immune surveillance and the maintenance of barrier integrity. Although the mechanisms controlling memory T cell migration to peripheral tissues are poorly understood, the current paradigm includes the localized secretion of "imprinting" signals from tissue-resident DCs in the draining lymph nodes. Here, we show that CCR8 expression by newly activated naïve T cells is regulated by skin-specific factor(s) derived primarily from epidermal keratinocytes, whereas co-culture with primary cells from skin-unrelated epithelia, including the mesothelium and small intestine, failed to so; thereby providing a mechanism for the preferential expression of CCR8 by skin-resident memory T cells. The keratinocyte-derived CCR8-inducing factor(s) were soluble, and independent of vitamins A and D. Furthermore, the induction of CCR8 under these conditions correlated with an increase in CLA expression. Our findings challenge current tissue homing paradigms, especially those involving CCR10, and emphasize the importance of steady-state epidermis rather than tissue-resident DCs in controlling the localization of memory T cells within human skin.
    Blood 10/2012; DOI:10.1182/blood-2012-05-433037 · 9.78 Impact Factor
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    Marlene Wolf, Bernhard Moser
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    ABSTRACT: The large family of chemoattractant cytokines (chemokines) embraces multiple, in part unrelated functions that go well beyond chemotaxis. Undoubtedly, the control of immune cell migration (chemotaxis) is the single, unifying response mediated by all chemokines, which involves the sequential engagement of chemokine receptors on migrating target cells. However, numerous additional cellular responses are mediated by some (but not all) chemokines, including angiogenesis, tumor cell growth, T-cell co-stimulation, and control of HIV-1 infection. The recently described antimicrobial activity of several chemokines is of particular interest because antimicrobial peptides are thought to provide an essential first-line defense against invading microbes at the extremely large body surfaces of the skin, lungs, and gastrointestinal-urinary tract. Here we summarize the current knowledge about chemokines with antimicrobial activity and discuss their potential contribution to the control of bacterial infections that may take place at the earliest stage of antimicrobial immunity. In the case of homeostatic chemokines with antimicrobial function, such as CXCL14, we propose an immune surveillance function in healthy epithelial tissues characterized by low-level exposure to environmental microbes. Inflammatory chemokines, i.e., chemokines that are produced in tissue cells in response to microbial antigens (such as pathogen-associated molecular patterns) may be more important in orchestrating the cellular arm in antimicrobial immunity.
    Frontiers in Immunology 07/2012; 3:213. DOI:10.3389/fimmu.2012.00213
  • 5th International Gamma Delta T cell conference, Freiburg Germany; 05/2012
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    ABSTRACT: Vγ9/Vδ2 T cells are a minor subset of T cells in human blood and differ from all other lymphocytes by their specific responsiveness to (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), a metabolite produced by a large range of microbial pathogens. Vγ9/Vδ2 T cells can be skewed towards distinct effector functions, in analogy to, and beyond, the emerging plasticity of CD4(+) T cells. As such, depending on the microenvironment, Vγ9/Vδ2 T cells can assume features reminiscent of Th1, Th2, Th17 and Treg cells as well as professional APCs. We here demonstrate that Vγ9/Vδ2 T cells express markers associated with follicular B helper T (T(FH) ) cells when stimulated with HMB-PP in the presence of IL-21. HMB-PP induces upregulation of IL-21R on Vγ9/Vδ2 T cells. In return, IL-21 plays a co-stimulatory role in the expression of the B-cell-attracting chemokine CXCL13, the CXCL13 receptor CXCR5 and the inducible co-stimulator by activated Vγ9/Vδ2 T cells, and enhances their potential to support antibody production by B cells. The interaction between HMB-PP-responsive Vγ9/Vδ2 T cells, IL-21-producing T(FH) cells and B cells in secondary lymphoid tissues is likely to impact on the generation of high affinity, class-switched antibodies in microbial infections.
    European Journal of Immunology 01/2012; 42(1):110-9. DOI:10.1002/eji.201142017 · 4.52 Impact Factor
  • Nature Immunology 11/2011; 12(11):1017-8; author reply 1018-20. DOI:10.1038/ni.2111 · 24.97 Impact Factor
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    Antimicrobial Agents and Chemotherapy 07/2011; 55(7):3635-6. DOI:10.1128/AAC.00382-11 · 4.57 Impact Factor

Publication Stats

17k Citations
930.80 Total Impact Points

Institutions

  • 2007–2015
    • Cardiff University
      • • School of Medicine
      • • Cardiff Institute of Infection & Immunity
      • • Department of Infection, Immunity and Biochemistry
      • • Department of Medical Biochemistry and Immunology
      Cardiff, Wales, United Kingdom
  • 2013
    • University of South Wales
      Понтиприте, Wales, United Kingdom
  • 1996–2007
    • Harvard Medical School
      • Department of Pathology
      Boston, Massachusetts, United States
  • 1996–2006
    • Universität Bern
      • • Institute of Cell Biology
      • • Theodor-Kocher Institute
      Bern, BE, Switzerland
  • 2005
    • Max Planck Institute of Molecular Cell Biology and Genetics
      Dresden, Saxony, Germany
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2000
    • University of Lausanne
      Lausanne, Vaud, Switzerland
  • 1992–1998
    • University of British Columbia - Vancouver
      • Biomedical Research Centre (BRC)
      Vancouver, British Columbia, Canada
  • 1996–1997
    • Institut Pasteur
      Lutetia Parisorum, Île-de-France, France