Yr Athro Ann Ager

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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.

2021

Brown, L. V., Gaffney, E. A., Ager, A., Wagg, J. and Coles, M. C. 2021. Quantifying the limits of CAR T-cell delivery in mice and men. Journal of the Royal Society Interface 18(176), article number: 20201013. (10.1098/rsif.2020.1013)

2020

Hughes, E. et al. 2020. Primary breast tumours but not lung metastases induce protective anti-tumour immune responses after Treg-depletion. Cancer Immunology, Immunotherapy 69, pp. 2063 - 2073. (10.1007/s00262-020-02603-x)
Demaria, M. C. et al. 2020. Tetraspanin CD53 promotes lymphocyte recirculation by stablising L-selectin surface expression. iScience 23(5), article number: 101104. (10.1016/j.isci.2020.101104)
Cerretelli, G., Ager, A., Arends, M. J. and Frayling, I. M. 2020. Molecular pathology of Lynch Syndrome. Journal of Pathology 250(5), pp. 518-531. (10.1002/path.5422)
Crowther, M. D. et al. 2020. Genome-wide CRISPR-Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1. Nature Immunology 21, pp. 178 - 185. (10.1038/s41590-019-0578-8)

2019

Pfuderer, P. L. et al. 2019. High endothelial venules are associated with microsatellite instability, hereditary background and immune evasion in colorectal cancer. British Journal of Cancer 121, pp. 395-404. (10.1038/s41416-019-0514-6)
Watson, H. A. et al. 2019. L-selectin enhanced T cells improve the efficacy of cancer immunotherapy. Frontiers in Immunology 10, article number: 1321. (10.3389/fimmu.2019.01321)
Mohammed, R. N. et al. 2019. ADAM17-dependent proteolysis of L-selectin promotes early clonal expansion of cytotoxic T cells. Scientific Reports 9, article number: 5487. (10.1038/s41598-019-41811-z)

2018

Seth, S., Ager, A., Arends, M. and Frayling, I. M. 2018. Lynch Syndrome - cancer pathways, heterogeneity and immune escape. Journal of Pathology 246(2), pp. 129-133. (10.1002/path.5139)
Jones, E., Gallimore, A. and Ager, A. 2018. Defining high endothelial venules and tertiary lymphoid structures in cancer. In: Tertiary Lymphoid Structures. Methods in Molecular Biology., Vol. 1845. Methods in Molecular Biology Humana Press, pp. 99-118., (10.1007/978-1-4939-8709-2_7)
Miles, J. J. et al. 2018. Peptide mimic for influenza vaccination using nonnatural combinatorial chemistry. Journal of Clinical Investigation 128(4), pp. 1569-1580. (10.1172/JCI91512)
Gaweł-Bęben, K., Ali, N., Ellis, V., Velasco, G., Poghosyan, Z., Ager, A. and Knauper, V. 2018. TMEFF2 shedding is regulated by oxidative stress and mediated by ADAMs and transmembrane serine proteases implicated in prostate cancer. Cell Biology International 42(3), pp. 273-280. (10.1002/cbin.10832)

2017

Caucheteux, S., Hu-Li, J., Mohammed, R., Ager, A. and Paul, W. 2017. Cytokine regulation of lung Th17 response to airway immunization using LPS adjuvant. Mucosal Immunology 10(2), pp. 361-372. (10.1038/mi.2016.54)
Ager, E. 2017. High endothelial venules and other blood vessels: critical regulators of lymphoid organ development and function. Frontiers in Immunology 8, article number: 45. (10.3389/fimmu.2017.00045)

2016

Watson, H. A. et al. 2016. Purity of transferred CD8+ T cells is crucial for safety and efficacy of combinatorial tumor immunotherapy in the absence of SHP-1. Immunology and Cell Biology 94(8) (10.1038/icb.2016.45)
Watson, H. A., Wehenkel, S., Matthews, J. and Ager, E. 2016. SHP-1: the next checkpoint target for cancer immunotherapy?. Biochemical Society Transactions 44(2), pp. 356-362. (10.1042/BST20150251)
Ager, E., Watson, H. A., Wehenkel, S. C. and Mohammed, R. N. 2016. Homing to solid cancers: a vascular checkpoint in adoptive cell therapy using CAR T-cells. Biochemical Society Transactions 44(2), pp. 377-385. (10.1042/BST20150254)
Mohammed, R. N., Watson, H. A., Vigar, M., Ohme, J., Thomson, A., Humphreys, I. R. and Ager, A. 2016. L-selectin is essential for delivery of activated CD8+ T cells to virus-infected organs for protective immunity. Cell Reports 14(4), pp. 760-771. (10.1016/j.celrep.2015.12.090)

2015

Ondondo, B. et al. 2015. A distinct chemokine axis does not account for enrichment of Foxp3+ CD4+T cells in carcinogen-induced fibrosarcomas. Immunology 145(1), pp. 94-104. (10.1111/imm.12430)
Ager, A. and May, M. J. 2015. Understanding high endothelial venules: lessons for cancer immunology. OncoImmunology 4(6), article number: e1008791. (10.1080/2162402X.2015.1008791)

2014

Ondondo, B. et al. 2014. Progression of carcinogen-induced fibrosarcomas is associated with the accumulation of naïve CD4+ T cellsviablood vessels and lymphatics. International Journal of Cancer 134(9), pp. 2156-2167. (10.1002/ijc.28556)

2012

Humphreys, I. R. et al. 2012. Avidity of influenza-specific memory CD8+T-cell populations decays over time compromising antiviral immunity. European Journal of Immunology 42(12), pp. 3235-3242. (10.1002/eji.201242575)
Hindley, J. P. et al. 2012. T-cell trafficking facilitated by high endothelial venules is required for tumor control after regulatory T cell depletion. Cancer Research 72(21), pp. 5473-5482. (10.1158/0008-5472.CAN-12-1912)
Ager, A. 2012. ADAMs and ectododomain proteolytic shedding in leucocyte migration: Focus on L-Selectin and ADAM17. Current Immunology Reviews 8(2), pp. 103-117. (10.2174/157339512800099657)

2009

Klinger, A., Gebert, A., Bieber, K., Kalies, K., Ager, A., Bell, E. B. and Westermann, J. 2009. Cyclical expression of L-selectin (CD62L) by recirculating T cells. International Immunology 21(4), pp. 443-455. (10.1093/intimm/dxp012)

2008

Anderson, B. E. et al. 2008. Effects of donor T-cell trafficking and priming site on graft-versus-host disease induction by naive and memory phenotype CD4 T cells. Blood 111(10), pp. 5242-5251. (10.1182/blood-2007-09-107953)
Sinclair, L. V. et al. 2008. Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nature Immunology 9(5), pp. 513-521. (10.1038/ni.1603)
Anderson, B. E. et al. 2008. Memory T Cells in GVHD and GVL. Biology of Blood and Marrow Transplantation 14(Supp.1), pp. 19-20. (10.1016/j.bbmt.2007.10.013)

2007

Ager, A., Galkina, E., Preece, G. and Lawrence, M. B. 2007. T lymphocyte rolling and recruitment into peripheral lymph nodes is regulated by a saturable density of L-selectin (CD62L). European Journal of Immunology 37(5), pp. 1243-1253. (10.1002/eji.200636481)

2004

Ivetic, A., Florey, O., Deka, J., Haskard, D. O., Ager, A. and Ridley, A. J. 2004. Mutagenesis of the ezrin-radixin-moesin binding domain of L-selectin tail affects shedding, microvillar positioning, and leukocyte tethering. Journal of Biological Chemistry 279(32), pp. 33263-33272. (10.1074/jbc.M312212200)

2003

Ager, A., Kioussis, D., Haskard, D. O. and Galkina, E. 2003. L-selectin shedding does not regulate constitutive T cell trafficking but controls the migration pathways of antigen-activated T lymphocytes. Journal of Experimental Medicine 198(9), pp. 1323-1335. (10.1084/jem.20030485)
Ager, A. 2003. Inflammation: border crossings. Nature 421(6924), pp. 703-705. (10.1038/421703a)

2002

Ivetic, A., Deka, J., Ridley, A. and Ager, A. 2002. The cytoplasmic tail of L-selectin interacts with members of the Ezrin-Radixin-Moesin (ERM) family of proteins: cell activation-dependent binding of Moesin but not Ezrin. The Journal of Biological Chemistry 277(3), pp. 2321-2329. (10.1074/jbc.M109460200)
Phillips, R. and Ager, A. 2002. Activation of pertussis toxin-sensitive CXCL12 (SDF-1) receptors mediates transendothelial migration of T lymphocytes across lymph node high endothelial cells. European Journal of Immunology 32(3), pp. 837-847. (10.1002/1521-4141(200203)32:3<837::AID-IMMU837>3.0.CO;2-Q)

2001

Ager, A., Faveeuw, C. and Preece, G. 2001. Transendothelial migration of lymphocytes across high endothelial venules into lymph nodes is affected by metalloproteinases. Blood 98(3), pp. 688-95. (10.1182/blood.V98.3.688)

2000

Faveeuw, C., Di Mauro, M. E., Price, A. A. and Ager, A. 2000. Roles of alpha4 integrins/VCAM-1 and LFA-1/ICAM-1 in the binding and transendothelial migration of T lymphocytes and T lymphoblasts across high endothelial venules. International Immunology 12(3), pp. 241-251. (10.1093/intimm/12.3.241)

1999

Derry, C. J., Faveeuw, C., Mordsley, K. R. and Ager, A. 1999. Novel chondroitin sulfate-modified ligands for L-selectin on lymph node high endothelial venules. European Journal of Immunology 29(2), pp. 419-430. (10.1002/(SICI)1521-4141(199902)29:02<419::AID-IMMU419>3.0.CO;2-A)
Borland, G., Murphy, G. and Ager, A. 1999. Tissue inhibitor of metalloproteinases-3 inhibits shedding of L-selectin from leukocytes. Journal of Biological Chemistry 274(5), pp. 2810-2815. (10.1074/jbc.274.5.2810)

1997

del Pozo, M. A., Cabañas, C., Montoya, M. C., Ager, A., Sánchez-Mateos, P. and Sánchez-Madrid, F. 1997. ICAMs redistributed by chemokines to cellular uropods as a mechanism for recruitment of T lymphocytes. Journal of Cell Biology 137(2), pp. 493-508. (10.1083/jcb.137.2.493)
Derry, C. J., Mordsley, K. R., Preece, G. and Ager, A. 1997. Purification of L-selectin ligands synthesised by rat peripheral lymph nodes and cultured high endothelial cells [Abstract]. Biochemical Society Transactions 25(2), article number: 260S.
Allport, J. R., Ding, H. T., Ager, A., Steeber, D. A., Tedder, T. F. and Luscinskas, F. W. 1997. L-selectin shedding does not regulate human neutrophil attachment, rolling, or transmigration across human vascular endothelium in vitro. Journal of Immunology 158(9), pp. 4365-4372.
Middelhoven, P. J., Ager, A., Roos, D. and Verhoeven, A. J. 1997. Involvement of a metalloprotease in the shedding of human neutrophil FcγRIIIB. FEBS Letters 414(1), pp. 14-18. (10.1016/S0014-5793(97)00959-9)
Price, A. A., Cumberbatch, M., Kimber, I. and Ager, A. 1997. α6 integrins are required for Langerhans cell migration from the epidermis. Journal of Experimental Medicine 186(10), pp. 1725-1735. (10.1084/jem.186.10.1725)
Faveeuw, C., Di Mauro, M. and Ager, A. 1997. Adhesion molecules used by T lymphoblasts to interact with cultured high endothelial cells [Abstract]. Biochemical Society Transactions 25(2), article number: 261S.

1996

Preece, G., Murphy, G. and Ager, A. 1996. Metalloproteinase-mediated regulation of L-selectin levels on leucocytes. Journal of Biological Chemistry 271(20), pp. 11634-11640. (10.1074/jbc.271.20.11634)
Middelhoven, H., Ager, A., Roos, D. and Verhoeven, A. J. 1996. Possible role of metalloprotease in the shedding of neutrophil Fc gamma RIIIb [Abstract]. Journal of Leukocyte Biology Supp S, pp. 174.
Middelhoven, P. J., Ager, A., Roos, D. and Verhoeven, A. J. 1996. Possible role of a metalloprotease in the shedding of neutrophil Fc gamma IIIb [Abstract]. Journal of Leukocyte Biology Supp S, pp. 169.
Ager, A. and Preece, G. 1996. The regulation of lymphocyte migration across high endothelial venules [Abstract]. Immunology 89(Supp1), pp. ST77.
Allport, J. R., Ding, H., Ager, A. and Luscinskas, F. W. 1996. Inhibition of L-selectin shedding does not affect human neutrophil attachment, rolling or transendothelial migration. Molecular Biology of the Cell 7, pp. 3502.
ParraRuiz, S. and Ager, A. 1996. Regulation of of integrins on rat lymphocytes [Abstract]. Immunology 89(Supp1), pp. 59., article number: T202.

1995

Bell, E. B., Sparshott, S. M. and Ager, A. 1995. Migration pathways of CD4 T cell subsets in vivo: the CD45RC- subset enters the thymus via α4 integrin-VCAM-1 interaction. International Immunology 7(11), pp. 1861-1871. (10.1093/intimm/7.11.1861)
Price, A. A., Kimber, I. and Ager, A. 1995. The expression of VLA-4 and VLA-6 by langerhans cells - their potential role in regulating langerhans cell-migration[Abstract]. Journal of Investigative Dermatology 105(6), pp. 858-869., article number: 64. (10.1111/1523-1747.ep12326705)

1994

Ager, A., Preece, G. and Wood, A. C. 1994. Down-regulation of lymphocyte L-selectin on binding to high endothelium - a prerequisite for transmigration [Abstract]. Journal of Cellular Biochemistry 56(S18A), pp. 331.
Ager, A. 1994. Lymphocyte recirculation and homing: roles of adhesion molecules and chemoattractants. Trends in Cell Biology 4(9), pp. 326-332. (10.1016/0962-8924(94)90234-8)

1993

Ager, A. 1993. Lymphocyte-vascular endothelial cell interactions in the immune response. Clinical and experimental immunology 93(Supp 1), pp. 5-6. (10.1111/j.1365-2249.1993.tb06213.x)
May, M. J., Entwistle, G., Humphries, M. J. and Ager, A. 1993. VCAM-1 is a CS1 peptide-inhibitable adhesion molecule expressed by lymph node high endothelium. Journal of Cell Science (JCS) 106(1), pp. 109-119.
Ensari, A., Ager, A., Marsh, M. N., Morgan, S. and Moriarty, K. J. 1993. Time-course of adhesion molecule expression in rectal mucosa of gluten-sensitive subjects after gluten challenge. Clinical and experimental immunology 92(2), pp. 303-307. (10.1111/j.1365-2249.1993.tb03396.x)
Hourihan, H., Allen, T. D. and Ager, A. 1993. Lymphocyte migration across high endothelium is associated with increases in alpha 4 beta 1 integrin (VLA-4) affinity. Journal of Cell Science (JCS) 104(4), pp. 1049-9.
Edwards, B. D., Slevin, M. A., Dickson, A. J., Ager, A. and Ballardie, W. 1993. Calphostin C inhibits endothelial cell proliferation and selectively modulates cell-surface marker expression [Abstract]. Biochemical Society Transactions 21(4), pp. 422S. (10.1042/bst021422s)
Edwards, B. D., Slevin, M. A., Dickson, A. J., Ager, A. and Ballardie, F. W. 1993. Antiproliferative actions of cyclosporin A on endothelial cells are not exerted through protein kinase C (PkC) [Abstract]. Biochemical Society Transactions 21(4), pp. 423S. (10.1042/bst021423s)
Bird, I. N., Spragg, J. H., Ager, A. and Matthews, N. 1993. Studies of lymphocyte transendothelial migration: analysis of migrated cell phenotypes with regard to CD31 (PECAM-1), CD45RA and CD45RO. Immunology 80(4), pp. 553-560.

1992

May, M. J. and Ager, A. 1992. ICAM-1-independent lymphocyte transmigration across high endothelium: differential up-regulation by interferon γ, tumor necrosis factor-α and interleukin 1β. European Journal of Immunology 22(1), pp. 219-226. (10.1002/eji.1830220132)
Ensari, A., Marsh, M. N., Ager, A., Morgan, S. and Moriarty, K. J. 1992. Expression of adhesion molecules in glutenchallenged, coeliac disease (CD) rectal mucosa. Gut 33(Supp 2), pp. S67.
Bradley, J. A. et al. 1992. Allograft rejection in Cd4+ T cell-reconstituted athymic nude rats-the nonessential role of host-derived Cd8+ cells1. Transplantation 53(2), pp. 477-482.
Szekanecz, Z., Humphries, M. J. and Ager, A. 1992. Lymphocyte adhesion to high endothelium is mediated by two beta 1 integrin receptors for fibronectin, alpha 4 beta 1 and alpha 5 beta 1. Journal of Cell Science (JCS) 101(4), pp. 885-894.

1991

Ager, A. and Humphries, M. J. 1991. Integrin alpha 4 beta 1: its structure, ligand-binding specificity and role in lymphocyte-endothelial cell interactions. Chemical Immunology 50, pp. 55-74.
Vaage, J. T., Dissen, E., Ager, A., Fossum, S. and Rolstad, B. 1991. Allospecific recognition of hemic cells in vitro by natural killer cells from athymic rats: evidence that allodeterminants coded for by single major histocompatibility complex haplotypes are recognized. European Journal of Immunology 21(9), pp. 2167-2175. (10.1002/eji.1830210927)

1990

Vaage, J. T., Dissen, E., Ager, A., Roberts, I., Fossum, S. and Rolstad, B. 1990. T cell receptor-bearing cells among rat intestinal intraepithelial lymphocytes are mainly α/β+ and are thymus dependent. European Journal of Immunology 20(5), pp. 1193-1196. (10.1002/eji.1830200538)
Ager, A. and Humphries, M. J. 1990. Use of synthetic peptides to probe lymphocyte – high endothelial cell interactions. Lymphocytes recognize a ligand on the endothelial surface which contains the CS1 adhesion motif. International Immunology 2(10), pp. 921-928. (10.1093/intimm/2.10.921)

1988

Ager, A., Fajumi, J., Sparshott, S. M., Ford, W. L. and Butcher, G. W. 1988. Major histocompatibility complex control of nk-related allogeneic lymphocyte cytotoxicity in rats the contributions of strong and medial transplantation antigens. Transplantation 46(5), pp. 762-767.
Ager, A. and Mistry, S. 1988. Interaction between lymphocytes and cultured high endothelial cells: an in vitro model of lymphocyte migration across high endothelial venule endothelium. European Journal of Immunology 18(8), pp. 1265-1274. (10.1002/eji.1830180818)
Ager, A. and Mistry, S. 1988. The expression of lymphocyte adhesion molecules on cultured high endothelial cells. Advances in Experimental Medicine and Biology 237, pp. 471-476.

1987

Ager, A. 1987. Isolation and culture of high endothelial cells from rat lymph nodes. Journal of Cell Science (JCS) 87(1), pp. 133-144.
Kumar, S., West, D. C. and Ager, A. 1987. Heterogeneity in endothelial cells from large vessels and microvessels. Differentiation 36(1), pp. 57-70. (10.1111/j.1432-0436.1987.tb00181.x)
Fossum, S., Ager, A. and Rolstad, B. 1987. Specific inhibition of natural killer (NK) activity against different alloantigens. Immunogenetics 26(6), pp. 329-338. (10.1007/BF00343700)

1985

Felce, D. J., Dekock, U., Thomas, M., Repp, A., Ager, A. and Blunden, R. 1985. Staff-client ratios and their effects on staff interactions and client behaviors [Abstract]. Bulletin of the British Psychological Society 38, pp. A61.

1984

Ager, A., Wenham, D. J. and Gordon, J. L. 1984. Stimulation of endothelial cells by protease activity in commercial preparations of xanthine oxidase. Thrombosis Research 35(1), pp. 43-52. (10.1016/0049-3848(84)90311-6)
Ager, A. and Gordon, J. L. 1984. Cellular effects of proteinase activity in commercial xanthine oxidase [Letter]. Biochemical Journal 222(3), pp. 839.
LeRoy, E. C., Ager, A. and Gordon, J. L. 1984. Effects of neutrophil elastase and other proteases on porcine aortic endothelial prostaglandin I2 production, adenine nucleotide release, and responses to vasoactive agents. The Journal of Clinical Investigation 74(3), pp. 1003-1010. (10.1172/JCI111467)
Ager, A. and Gordon, J. L. 1984. Differential effects of hydrogen peroxide on indices of endothelial cell function. Journal of Experimental Medicine 159(2), pp. 592-603. (10.1084/jem.159.2.592)

1983

Ager, A. and Martin, W. 1983. Loss of receptor-mediated 86Rb efflux from pig aortic endothelial cells in culture. British Journal of Pharmacology 80(1), pp. 5-6. (10.1111/j.1476-5381.1983.tb11040.x)
Chesterman, C. N., Ager, A. and Gordon, J. L. 1983. Regulation of prostaglandin production and ectoenzyme activities in cultured aortic endothelial cells. Journal of Cellular Physiology 116(1), pp. 45-50. (10.1002/jcp.1041160108)

1982

Ager, A., Gordon, J. L., Moncada, S., Pearson, J. D., Salmon, J. A. and Trevethick, M. A. 1982. Effects of isolation and culture on prostaglandin synthesis by porcine aortic endothelial and smooth muscle cells. Journal of Cellular Physiology 110(1), pp. 9-16. (10.1002/jcp.1041100103)
Ager, A. 1982. Effects of xanthine: xanthine oxidase on membrane function: an in vitro model of endothelial damage. Agents and Actions Supplements 11, pp. 73-81.

1981

Ager, A. and Gordon, J. L. 1981. Influence of human β-thromboglobulin on prostaglandin production by pig aortic endothelial cells in culture. Thrombosis Research 24(1-2), pp. 95-103. (10.1016/0049-3848(81)90035-9)

1980

Ager, A. and Gordon, J. L. 1980. Effects of vasoactive and inflammatory agents on cyclic AMP levels in W 138 fibroblasts, endothelial and vascular smooth muscle cells in culture. Agents and Actions 10(6), pp. 569-572.

1979

Pearson, J. D., Ager, A., Trevethick, M. A. and Gordon, J. L. 1979. Prostaglandin production by cultured vascular cells. Agents and Actions Supplements 4, pp. 120-126.
Ager, A., Pearson, J. D. and Gordon, J. L. 1979. Radioimmunoassay of 6-oxoprostaglandin F1α and prostaglandin E2 produced by pig aortic endothelium in culture [Abstract]. Biochemical Society Transactions 7(5), pp. 1065-1066. (10.1042/bst0071065)

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

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

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