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Professor Ann Ager

Professor Ann Ager

Personal Chair

School of Medicine

Email:
agera@cardiff.ac.uk
Telephone:
+44 (0)29 2068 8872
Location:
3F08, Henry Wellcome Building for Biomedical Research, University Hospital of Wales, Heath Park, Cardiff, CF14 4XN

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 (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 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.

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

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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