Ewch i’r prif gynnwys
Ann Ager

Yr Athro Ann Ager

Reader

Yr Ysgol Meddygaeth

Email
AgerA@caerdydd.ac.uk
Telephone
+44 29206 88872
Campuses
Adeilad Henry Wellcome ar gyfer Ymchwil Biofeddygol, Ystafell 3F08, Ysbyty Athrofaol Cymru, Parc y Mynydd Bychan, Caerdydd, CF14 4XN

Trosolwyg

The focus of the Ager lab is how leucocytes move around the body in order to protect against infection, fight cancer and contribute to neurodegeneratiion such as in Alzheimer's disease. This has resulted in a body of work studying the molecular basis of T lymphocyte-blood endothelial cell recognition which directs lymphocyte trafficking to organised lymphoid tissues and sites of infection and immunity. A major focus has been the regulation of L-selectin expression on T lymphocytes and its impact  on physiological and pathological T cell trafficking via specialised high endothelial venule (HEV) blood vessels. Recent studies have revealed an essential role for L-selectin in the recruitment of killer T cells into flu-infected lungs for virus clearance which was highlighted by the BBC (http://www.bbc.co.uk/news/uk-wales-south-east-wales-35373730).  Current studies are exploring pharmacological and genetic approaches to boost L-selectin expression on  T lymphocytes to help killer T cells find and destroy other viruses. We are also exploring whether manipulating L-selectin on cancer-killing T lymphocytes, such as CAR-T cells, increases their ability to seek out and destroy solid cancers.

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Articles

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Ymchwil

Manipulating T lymphocyte homing to control cancer, virus infection, autoimmunity and neurodegeneration

Effective immune responses and the regulated homing of T lymphocytes are inextricably linked.  Naïve lymphocytes recirculate through lymph nodes via the bloodstream and lymphatics in search of antigen. Long-lasting, protective immunity also depends on the homing of central memory T cells to lymph nodes where they receive signals for differentiation and survival.  High endothelial venules (HEV) play a critical role in this process by selecting lymphocytes from the total pool of circulating leucocytes for entry into lymph nodes.  The adhesion molecule L-selectin/CD62L mediates the capture of lymphocytes from flowing blood onto the endothelial cell lining of HEV which constitutively express peripheral node addressin, a ligand for L-selectin.

L-selectin and T lymphocyte activation

L-selectin expression is tightly linked to the state of T cell differentiation, being highly expressed on naïve and central memory T cells and downregulated on effector and effector memory T cells. Lselectin expression is regulated by two non-overlapping mechanisms, ectodomain proteolysis by ADAMs metalloproteinases (shedding) and gene silencing, but their roles in regulating T cell trafficking and function are not known. To dissect the relative contributions of shedding and gene silencing, we generated genetically modified mice in which shedding and/or gene silencing of Lselectin is abrogated in T cells. Under homeostatic conditions T cells unable to downregulate L-selectin are recruited into lymph node nodes in normal numbers, however, T cells unable to shed L-selectin take longer to transmigrate HEV (Galkina, et al., J Exp Med,198:1323, 2003; Faveeuw et al. Blood, 98:688, 2001).   The impact of TCR induced downregulation of L-selectin in shaping the immune response has been studied using experimental mouse models of immunity to tumours and viruses. As expected, maintenance of L-selectin at the surface of activated T cells, by inhibiting either shedding or gene silencing, maintains their ability to enter lymph nodes (Galkina, et al., J Exp Med.198:1323, 2003; Galkina et al., Eur J Immunol 37:1243, 2007; Sinclair, L.V., et al., Nat Immunol. 9:513, 2008). Downregulation of L-selectin is not required for CD8+ T cell differentiation or for migration of effector/effector memory CD8 T cells to non-lymphoid tissues or to infected organs (Richards, H., et al., J Immunol, 180:198, 2008). However, maintained expression of L-selectin on effector and memory T cells has revealed dramatic effects on T cell dependent immunity.  CD8+ T cell dependent protective immunity to viral infection and tumours are enhanced.

High Endothelial Venules (HEV) neogenesis

Outside of lymph nodes, HEV are induced in tissues undergoing autoimmune reactions such as in rheumatoid arthritis, Sjorgren’s syndrome and type 1 diabetes (Drayton, D.L., et al., Nat Immunol, 7:344, 2006).  It is thought that HEV are detrimental to the disease process by allowing the entry of self-reactive lymphocytes which cause tissue destruction.  HEV are also induced in solid tumours where they are thought to be beneficial, allowing effector lymphocytes to invade and destroy the tumour (Martinet, L., et al., Cancer Res. 71:5678, 2011; Ager & May, OncoImmunology, 2015).  The development of HEV may overcome one of the barriers to effective immunotherapy of neovascularised cancers in which the tumour microenvironment actively restricts the recruitment of cytotoxic, effector T lymphocytes (Buckanovich et al, Nat Med 14, 28-36).  Identification of the mechanisms that induce and maintain blood vessel differentiation along the HEV pathway outside of lymph nodes will be important to unravel these human diseases.

Major goals for the future are to identify the mechanisms underlying L-selectin dependent anti-viral and anti-tumour immunity and whether this is dependent on HEV neogenesis in the target organ.   Endothelial cells lining HEV rapidly dedifferentiate following isolation from, or manipulation of, their intact tissue environment. Lymphotoxin-β receptor activation of non-canonical NF-κB signalling in endothelial cells (EC) via lymphotoxin expressing dendritic cells has been shown to maintain HEV function in lymph nodes (Browning et al, Immunity, 23:539, 2005; Moussion, C. and J.P. Girard, Nature. 479: 542, 2011) but the receptors and ligands that drive EC differentiation in tumours and automimmune diseases are poorly understood (Ager & May, OncoImmunology, 2015). We are using EC isolated from non-lymphoid organs and soluble and cell-associated activators of non-canonical NF-κB signalling to establish in vitro models of endothelial cell activation and differentiation along the HEV pathway. The expression of inflammation- and HEV-associated markers will be determined by protein and gene expression analysis. The impact of endothelial activation and differentiation on the recruitment of cytotoxic, effector CD8+ T cells will be determined under conditions that mimic blood flow. Defined populations of tumour cells, stromal cells and tissue-infiltrating leucocytes from diseased tissues will be co-cultured with EC and the impact on EC activation and differentiation determined.

Translational impact

Our basic studies of T lymphocyte homing via HEV have revealed a novel approach to controlling immunity by modulating T cell trafficking.  Increasing the recruitment of tumour-specific effector T cells into cancerous tissues by promoting T cell homing and/or inducing blood vessel differentiation is important in order to overcome the block to immunotherapy imposed by poor recruitment of effector T cells by tumour blood vessels. This strategy can be viewed as an adjunct to approaches currently being trialled in the clinic, such as therapeutic vaccination, adoptive T cell therapy and antibodies to CTLA4 and PD-1. Identification of the mechanisms underlying the differentiation of endothelial cells along the HEV pathway may reveal potential therapeutic targets to inhibit blood vessel differentiation in autoimmunity and limit T cell infiltration and ongoing disease. Conversely, blood vessel differentiation along the HEV pathway in tumours may provide opportunities to promote T cell infiltration and tumour destruction.

Examples of Grant Fundng:

1. MRC Project Grant “Dissecting the impact of L-selectin on T lymphocyte dependent tumour immunity” Lead PI (October 2014-April 2018) £ 529,291

2. GE-Healthcare “Longitudinal monitoring of T lymphocyte migration in vivo” (2015-2016) Lead PI £21,571.

3. CR-UK Cardiff Centre Development Fund “Longitudinal monitoring of T lymphocyte migration in vivo using Positron Emission Tomography-Computed tomography (PET-CT)” (2015-2016) Lead PI £6,926.

4. Neuroscience and Mental Health Institute PhD studentship, Cardiff University. “Mapping changes to vascular health in Alzheimer’s disease” Co-PI (2015-2018) £ 85,498

5. Wellcome Trust Enhancement “Regulation of T cell functions by enzymatic proteolysis of L-selectin”. Sole PI (2015-2017) £68,092.

6. MRC/Cardiff University School of Medicine PhD Studentship. “The Regulation of L-selectin Activity by Proteolysis”. PI (October 2013-April 2017) £60,000

7. Wellcome Trust Project Grant “Manipulating T lymphocyte homing and activation for cancer immunotherapy.” (2011-2017) Lead PI £313,321

8. Wales Cancer Research Centre “Preclinical models for novel immunotherapies using MHC restricted and non-restricted T cells” 2015- 2018 Co-PI £85,000

9. School of Medicine PhD studentship. Engineering homing properties of cancer-specfic T lymphocytes in adoptive cell therapy 2017-2020 Lead supervisor £80,000

Addysgu

External lectures:

Ager, A. (2020, October 29). Lymphocyte homing: getting lymphocytes to the right place at the right time. In The Biomedical & Life Sciences Collection, Henry Stewart Talks.   https://hstalks.com/bs/4445/.

Taught courses:

  • Deliver Student Selected Component (SSC) in Interactive Immunology to 2nd and 3rd year medical students (lead laboratory sessions, review student presentation, deliver lectures).
  • Deliver 3rd year BSc and Medical Intercalated Degree students in Pharmacology and Pathology (supervised 7 students’ laboratory projects; best project by Louise Rogers, 2017. Danial Saree, 2019)
  • Deliver taught Masters in Research (supervised 6 students and recruited one, Andrew Newman to study for a PhD under my supervision)
  • Develop teaching skills of my PhD students and PDRAs by supporting their supervision of final year B.Sc. project students in a co-supervisory role.

    Examining experience:

    • External examiner for Manchester University’s Master degrees in Immunology and Immunogenetics, (15-20 students p.a.) and Immunology by distance learning (5-10 students p.a.) 2012-2016 
    • External examiner of PhD theses for the Universities of Birmingham, Bristol, Dundee, Glasgow, Imperial College London, KCL, Oxford, Sheffield, Toronto and Australian National University

    Bywgraffiad

    Career Summary

    After gaining a PhD from Cambridge University studying inflammatory responses in vascular endothelial cells, Dr Ager moved to Professor Judah Folkman’s laboratory at Harvard to train in microvascular endothelial cell biology. She then moved to Professor Bill Ford’s laboratory in Manchester to study the regulation of lymphocyte trafficking by high endothelial venules (HEV) where she gained a non-clinical MRC Senior Fellowship before moving to the MRC National Institute for Medical Research. The focus of the Ager lab has been the molecular basis of lymphocyte-HEV recognition. This has resulted in a body of work based on a tractable in vitro model of lymphocyte-HEV recognition and studies of lymphocyte trafficking and immune responses in genetically modified mice developed by Dr Ager. A major focus has been the regulation of Lselectin expression and its impact on physiological and pathological T cell trafficking  in virus infection, cancer, and, more recently, Alzheimer's disease.  

    Employment

    Current:          2007-present Reader, Infection and Immunity, School of Medicine, Cardiff University                              HEFCW (f/t)

    Previous

    1992 - 2007   Senior Scientist, Division of Cellular Immunology, MRC National Institute for Medical Research,

    1987 - 1992     MRC Senior Fellow, Immunology Department, University of Manchester

    1983 - 1987     MRC Post-doctoral Fellow, Immunology Department, University of Manchester

    1980 - 1983     BBSRC Post-doctoral Fellow, Department of Cell Biology, The Babraham Institute

    1979 - 1980     BHF Travelling Fellow, Childrens’ Hosptial, Harvard Medical School, USA

    Anrhydeddau a dyfarniadau

    1979 - 1980     BHF Travelling Fellow, Childrens’ Hosptial, Harvard Medical School, USA

    2015-2018     President, UK Cell Adhesion Society (elected)

    2019- 2022    British Society for Immunology, Chair of Forum (elected)

    2019- 2022    British Society for Immunology, Member of Board of Trustees (elected)

    2019- 2022    National Cancer Research Institute-British Society of Immunology Strategic Alliance, Deputy Chair

    Aelodaethau proffesiynol

    Member of the British Society for Immunology

    Founding member of the UK Cell Adhesion Society

    Member of Cardiff Institute for Tissue Engineering and Repair (CITER)

    Safleoedd academaidd blaenorol

    B2007- 2018    Reader, Infection and Immunity, School of Medicine, Cardiff University

    1992 - 2007   Senior Scientist, Division of Cellular Immunology, MRC National Institute for Medical Research,

    1987 - 1992     MRC Senior Fellow, Immunology Department, University of Manchester

    1983 - 1987     MRC Post-doctoral Fellow, Immunology Department, University of Manchester

    1980 - 1983     BBSRC Post-doctoral Fellow, Department of Cell Biology, The Babraham Institute

    Meysydd goruchwyliaeth

    • T lymphocyte homing in health and disease
    • Lymphocyte-blood vessel interactions in lymphoid organs and inflamed tissues
    • The role of blood brain barrier in neurodegeneration
    • Therapeutic manipulation of T lymphocyte homing to boost immunity to viruses and cancer

    Ymgysylltu

    2021   'How COVID-19 vaccines work' in public meeting organised by EMWWH and the Learned Society for Wales

    2020    I’m A Scientist, Health Zone STEM engagement activity connecting schools students with scientists

    2020    Coordinated meeting of the British Society for Immunology and the Chief Scientific Advisor (Health) for Wales to discuss Wales’ experience and practice in vaccination strategies in preparation for delivery of a Covid-19 vaccine

    2019    Hosted Secretary of State for Wales at the Parliamentary Links day on ‘Science and the New Frontiers’ and discussed investment opportunities in Wales in precision and regenerative medicine for economic growth and specialist education/training

    2018      Speaker at Pint of Science, ‘Immune cells: right place, right time’, Cardiff

    2017       Speaker at Soapbox Science on 10th June 2017 in Cardiff showcasing women in Science (https://www.cardiff.ac.uk/news/view/798209-soapbox-science-cardiff-2017)

    2017       Interactive practical demonstration of T cell trafficking at ‘Tackling Cancer Together’ open day organised by the Wales Cancer Partnership, Cardiff, 25th November 2017 (https://www.walescancerpartnership.com/partner-events/2017/11/25/tackling-cancer-together/)

    2017-2020       Interviews about my research and career for Wales radio (https://radiocardiff.org/pythagoras-trousers/), Cancer Research UK website and BBC Television Wales

    2016              Women’s Institute, Vale of Glamorgan: T-cells in immunity to viruses and cancers

    2016          Wellcome Inspire team Taster Days to Medical and Dental Students year to educate, inform and inspire students about biomedical research

    2014      Cancer Research UK Cardiff Centre Open Day: Presentation entitled ‘Of Mice and Men’ explaining translation of biomedical research to the clinic

    2013    Speaker at Science in Health Live that hosts 500 Year 12 pupils from schools across Wales and the border counties "Directing the traffic; how to white blood cells know where to go?’. (https://vimeo.com/channels/312286/73863788). Student feedback included ‘The best part was the short talk about white blood cells as it helped to put more information onto what I have already learnt in school’