Jean Fletcher
Ussher Ast Prof Translational Immunology, Biochemistry
Ussher Ast Prof Translational Immunology, Clinical Medicine

Publications and Further Research Outputs

Peer-Reviewed Publications

Sharee A. Basdeo, Deborah Cluxton, Jamal Sulaimani, Barry Moran, Mary Canavan, Carl Orr, Douglas J. Veale, Ursula Fearon and Jean M. Fletcher, Ex-Th17 (Nonclassical Th1) Cells Are Functionally Distinct from Classical Th1 and Th17 Cells and Are Not Constrained by Regulatory T Cells., J immunology, 198 , (2), 2017, p2249 - 2259 Journal Article, 2017 DOI

Dunne M, Ryan C, Tosetto M, Nolan B, Geraghty R, Winter DC, O'Connell R, Hyland J, Doherty GA, Sheahan K, Ryan EJ, Fletcher JM., Enrichment of inflammatory IL-17 and TNF-α secreting CD4+ T cells within colorectal tumours despite the presence of elevated CD39+ T regulatory cells and increased expression of the immune checkpoint molecule, PD-1., Frontiers in Oncology, 6, 2016, p50- Journal Article, 2016 URL TARA - Full Text

Basdeo S.A, Campbell N.K, Sullivan L.M, Flood B, Creagh E.M, Mantle T.J, Fletcher J.M, Dunne A, Suppression of human alloreactive T cells by linear tetrapyrroles; relevance for transplantation, Translational Research, 178, 2016, p81-94.e2 Journal Article, 2016 URL TARA - Full Text DOI

2. Basdeo SA, Kelly S, O'Connell K, Tubridy N, McGuigan C, Fletcher JM, Increased expression of Tbet in CD4+ T cells from clinically isolated syndrome patients at high risk of conversion to clinically definite MS. , Springer Plus, 5, 2016, p779- Journal Article, 2016 URL TARA - Full Text

Neuroinflammatory Disorders in, editor(s)Orla Hardiman, Colin P. Doherty, Marwa Elami, Peter Bede , Neurodegenerative Disorders, Springer International Publishing, 2016, pp269 - 287, [Costelloe C, Fletcher JM, Fitzgerald D. Neuroinflammatory Disorders. (In Neurodegenerative Disorders).] Book Chapter, 2016

Basdeo, S.A., Moran, B., Cluxton, D., (...), Fearon, U., Fletcher, J.M., Polyfunctional, pathogenic CD161+ Th17 lineage cells are resistant to regulatory T cell-mediated suppression in the context of autoimmunity, Journal of Immunology, 195, (2), 2015, p528-540 Journal Article, 2015 DOI

Kelly, A., Fahey, R., Fletcher, J.M., Keogh, C., Carroll, A.G., Siddachari, R., Geoghegan, J., Hegarty, J.E., Ryan, E.J., O'Farrelly, C., CD141+ myeloid dendritic cells are enriched in healthy human liver, Journal of Hepatology, 60, (1), 2014, p135-142 Journal Article, 2014 DOI

O'Connell K, Kelly S, Kinsella K, Jordan S, Kenny O, Murphy D, Heffernan E, O'Laoide R, O'Shea D, McKenna C, Cassidy L, Fletcher J, Walsh C, Brady J, McGuigan C, Tubridy N, Hutchinson M, Dose-related effects of vitamin D on immune responses in patients with clinically isolated syndrome and healthy control participants: study protocol for an exploratory randomized double- blind placebo-controlled trial., Trials, 14, 2013, p272 Journal Article, 2013 TARA - Full Text DOI

Fletcher, J., Hutchinson, M., Tubridy, N., Response to comment on the article by Allen et al. 'A pilot study of the immunological effects of high-dose vitamin D in healthy volunteers', Multiple Sclerosis , 19, (4), 2013, p509 Journal Article, 2013 DOI

Immunology of Multiple Sclerosis in, The Biology of Multiple Sclerosis, Cambridge University Press, 2012, pp1-146 , [Fletcher JM and Mills KHG] Book Chapter, 2012 URL

Jean M Fletcher, Sharee A Basdeo, Aideen C Allen and Padraic J Dunne, Therapeutic use of vitamin D and its analogues in autoimmunity, Recent Patents in Inflammation Allergy Drug Discovery, 6, (1), 2012, p22 - 34 Journal Article, 2012

Allen AC, Kelly S, Basdeo SA, Kinsella K, Mulready KJ, Mills KH, Tubridy N, Walsh C, Brady JJ, Hutchinson M, Fletcher JM, A pilot study of the immunological effects of high-dose vitamin D in healthy volunteers., Multiple sclerosis (Houndmills, Basingstoke, England), 18, (12), 2012, p1797 - 1800 Journal Article, 2012 DOI

Lalor, S.J., Dungan, L.S., Sutton, C.E., Basdeo, S.A., Fletcher, J.M., Mills, K.H.G., Caspase-1-processed cytokines IL-1β and IL-18 promote IL-17 production by γδ and CD4 T cells that mediate autoimmunity, Journal of Immunology, 186, (10), 2011, p5738-5748 Journal Article, 2011 DOI

Cheryl M. Sweeney, Roisin Lonergan, Sharee A. Basdeo, Katie Kinsella, Lara S. Dungan, Sarah C. Higgins, Patrick J. Kelly, Lisa Costelloe, Niall Tubridy, Kingston H.G. Mills, Jean M. Fletcher, IL-27 mediates the response to IFN beta therapy in multiple sclerosis patients by inhibiting Th17 cells, Brain, Behavior, and Immunity, 25, (6), 2011, p1170-1181 Journal Article, 2011 TARA - Full Text

Hoare M, Gelson WT, Das A, Fletcher JM, Davies SE, Curran MD, Vowler SL, Maini MK, Akbar AN, Alexander GJ., CD4+ T-lymphocyte telomere length is related to fibrosis stage, clinical outcome and treatment response in chronic hepatitis C virus infection., Journal of Hepatology, 53, (2), 2010, p252 - 260 Journal Article, 2010 TARA - Full Text

O'Brien M, Lonergan R, Costelloe L, O'Rourke K, Fletcher JM, Kinsella K, Sweeney C, Antonelli G, Mills KH, O'Farrelly C, Hutchinson M, Tubridy N. , OAS1: a multiple sclerosis susceptibility gene that influences disease severity., Neurology, 75, (5), 2010, p411 - 418 Journal Article, 2010 DOI

Fletcher, J.M., Lalor, S.J., Sweeney, C.M., Tubridy, N., Mills, K.H.G, T cells in multiple sclerosis and experimental autoimmune encephalomyelitis , Clinical and Experimental Immunology, 162, (1), 2010, p1-11 Journal Article, 2010 TARA - Full Text

Fletcher JM, Lonergan R, Costelloe L, Kinsella K, Moran B, O'Farrelly C, Tubridy N, Mills KH, CD39+Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis., Journal of Immunology , 183, (11), 2009, p7602-7610 Journal Article, 2009 TARA - Full Text DOI

IL-10 and TGF-beta-producing regulatory T cells in infection in, editor(s)Shuiping Jiang , Regulatory cells and Clinical Application, Springer Science and Business Media, LLC , 2008, pp423 - 453, [Dunne PJ, Rowan A, Fletcher JM and KHG Mills] Book Chapter, 2008

Jarnicki, AJ, Conroy, H. Brereton, C, Donnelly, G., Toomey, D., Walsh, K.,, Sweeney, C., Leavy, O., Fletcher, J., Lavelle, E., Dunne, P. and Mills, K.H.G., Attenuating regulatory T cell induction by TLR agonists through inhibition of p38 MAPK signaling in dendritic cells enhances their efficacy as vaccine adjuvants and cancer immunotherapeutics, Journal of Immunology, 180, (6), 2008, p3797 - 3806 Journal Article, 2008 TARA - Full Text URL

Van Baarle, D., Nanlohy, N.M., Otto, S., Plunkett, F.J., Fletcher, J.M., Akbar, A.N., Progressive telomere shortening of Epstein-Barr virus-specific memory T cells during HIV infection: Contributor to exhaustion, Journal of Infectious Diseases, 198, (9), 2008, p1353-1357 Journal Article, 2008 DOI

Rowan AG, Fletcher JM, Ryan EJ, Moran B, Hegarty JE, O'Farrelly C and Mills KHG, Hepatitis C virus-specific Th17 cells are suppressed by virus-induced TGF-beta, Journal of Immunology, 181, (7), 2008, p4485 - 4494 Journal Article, 2008 TARA - Full Text URL

Colonna-Romano G, Akbar AN, Aquino A, Bulati M, Candore G, Lio D, Ammatuna P, Fletcher JM, Caruso C, Pawelec G. , Impact of CMV and EBV seropositivity on CD8 T lymphocytes in an old population from West-Sicily., Experimental Gerontology, 42, (10), 2007, p995-1002. Journal Article, 2007 DOI

Plunkett FJ, Franzese O, Finney HM, Fletcher JM, Belaramani LL, Salmon M, Dokal I, Webster D, Lawson AD, Akbar AN., The loss of telomerase activity in highly differentiated CD8+CD28-CD27- T cells is associated with decreased Akt (Ser473) phosphorylation., Journal of Immunology , 178, (12), 2007, p7710-7719 Journal Article, 2007 URL

Vukmanovic-Stejic M, Zhang Y, Cook JE, Fletcher JM, McQuaid A, Masters JE, Rustin MH, Taams LS, Beverley PC, Macallan DC, Akbar AN., Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo., Journal of Clinical Investigation, 116, (9), 2006, p2423-2433. Journal Article, 2006 DOI

Dunne PJ, Belaramani L, Fletcher JM, Fernandez de Mattos S, Lawrenz M, Soares MV, Rustin MH, Lam EW, Salmon M, Akbar AN, Quiescence and functional reprogramming of Epstein-Barr virus (EBV)-specific CD8+ T cells during persistent infection. , Blood, 106, (2), 2005, p558-565 Journal Article, 2005 DOI

Fletcher JM, Vukmanovic-Stejic M, Dunne PJ, Birch KE, Cook JE, Jackson SE, Salmon M, Rustin MH, Akbar AN., Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion., Journal of Immunology , 175, (12), 2005, p8218-8225 Journal Article, 2005 URL

Plunkett FJ, Franzese O, Belaramani LL, Fletcher JM, Gilmour KC, Sharifi R, Khan N, Hislop AD, Cara A, Salmon M, Gaspar HB, Rustin MH, Webster D, Akbar AN. , The impact of telomere erosion on memory CD8+ T cells in patients with X-linked lymphoproliferative syndrome., Mechanisms of Ageing and Development, 126, (8), 2005, p855-865 Journal Article, 2005 DOI

Akbar AN, Fletcher JM., Memory T cell homeostasis and senescence during aging., Current Opinion in Immunology, 17, (5), 2005, p480-485 Journal Article, 2005 DOI

Soares MV, Plunkett FJ, Verbeke CS, Cook JE, Faint JM, Belaramani LL, Fletcher JM, Hammerschmitt N, Rustin M, Bergler W, Beverley PC, Salmon M, Akbar AN., Integration of apoptosis and telomere erosion in virus-specific CD8+ T cells from blood and tonsils during primary infection., Blood., 103, (1), 2004, p162-167 Journal Article, 2004 DOI

Reed JR, Vukmanovic-Stejic M, Fletcher JM, Soares MV, Cook JE, Orteu CH, Jackson SE, Birch KE, Foster GR, Salmon M, Beverley PC, Rustin MH, Akbar AN. , Telomere erosion in memory T cells induced by telomerase inhibition at the site of antigenic challenge in vivo., Journal of Experimental Medicine, 199, (10), 2004, p1433-1443 Journal Article, 2004 DOI

Lantto J, Fletcher JM, Ohlin M., Binding characteristics determine the neutralizing potential of antibody fragments specific for antigenic domain 2 on glycoprotein B of human cytomegalovirus, Virology., 305, (1), 2003, p201-209 Journal Article, 2003 DOI

*Lantto J, *Fletcher JM, Ohlin M. , A divalent antibody format is required for neutralization of human cytomegalovirus via antigenic domain 2 on glycoprotein B, Journal of General Virology, 83, (8), 2002, p2001-2005 Journal Article, 2002 URL

Taams, L.S., Vukmanovic-Stejic, M., Smith, J., Dunne, P.J., Fletcher, J.M., Plunkett, F.J., Ebeling, S.B., (...), Akbar, A.N., 17. Taams LS, Vukmanovic-Stejic M, Smith J, Dunne PJ, Fletcher JM, Plunkett FJ, Ebeling SB, Lombardi G, Rustin MH, Bijlsma JW, Lafeber FP, Salmon M, Akbar AN. Antigen-specific T cell suppression by human CD4+CD25+ regulatory T cells., European Journal of Immunology, 32, (6), 2002, p1621-1630 Journal Article, 2002 DOI

Dunne PJ, Faint JM, Gudgeon NH, Fletcher JM, Plunkett FJ, Soares MV, Hislop AD, Annels NE, Rickinson AB, Salmon M, Akbar AN., Epstein-Barr virus-specific CD8(+) T cells that re-express CD45RA are apoptosis-resistant memory cells that retain replicative potential., Blood, 100, (3), 2002, p933-940. Journal Article, 2002 DOI

Marais, G.I., Fletcher, J.M., Potter, P.C., In vivo and in vitro diagnosis of latex allergy at Groote Schuur Hospital , Ugeskrift for Laeger , 161, (29), 1999, p1004-1008 Journal Article, 1999

Fletcher JM, Prentice HG, Grundy JE., Natural killer cell lysis of cytomegalovirus (CMV)-infected cells correlates with virally induced changes in cell surface lymphocyte function-associated antigen-3 (LFA-3) expression and not with the CMV-induced down-regulation of cell surface class I HLA. , Journal of Immunology, 161, (5), 1998, p2365-2374 Journal Article, 1998 URL

Grundy JE, Lawson KM, MacCormac LP, Fletcher JM, Yong KL., Cytomegalovirus-infected endothelial cells recruit neutrophils by the secretion of C-X-C chemokines and transmit virus by direct neutrophil-endothelial cell contact and during neutrophil transendothelial migration, Journal of Infectious Diseases, 177, (6), 1998, p1465-1474. Journal Article, 1998 DOI

Research Expertise

Description

Research interests are focused on immune regulation in human disease. In a healthy immune system there is a balance between the pro-inflammatory responses necessary to fight infection and regulatory responses which keep these in check and maintain tolerance. Regulatory T (Treg) cells play a crucial role in maintaining peripheral tolerance, and depletion of these cells in mice results in autoimmunity. In recent years there has been much interest in Th17 cells, which are thought to play an important role in autoimmunity. The regulation of Th17 cells by Treg cells and immunomodulatory therapies is a key area of our research interest. We are interested in understanding how immune responses are dysregulated in autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA). During the past few years we have investigated the regulation of Th17 cells by natural Treg cells in MS. We showed that a particular subset of Treg cells expressing the CD39 marker could suppress Th17 cells, while in contrast CD39- Treg cells actually produced IL-17. These findings highlighted an important theme in immunology, namely that considerable plasticity exists within the T helper and Treg CD4 T cell subsets. Th17 cells can convert to Th1/Th17 cells or Th17 cells, and Treg cells can switch to Th17 cells under inflammatory conditions. Furthermore, we showed that both the frequency and function of CD39+ Treg cells was impaired in MS. This research is part of a longstanding collaboration with Prof. Niall Tubridy and his team at SVUH. We are also investigating the plasticity of Treg and Th17 cells and how this might contribute to autoimmune inflammation in the RA joint. This research is in collaboration with Dr Ursula Fearon and Prof. Doug Veale at SVUH. The role of CD39+ Treg cells in colorectal cancer is also being investigated in collaboration with Dr Liz Ryan, SVUH. We also have a research interest in investigating the immunomodulatory effects of various therapies in MS. The role of endogenous and exogenous IFN-beta in MS is one area of interest. We have previously shown that IFN-beta exerts various immunomodulatory effects on Th17-related cytokines and specifically induced IL-27 which inhibits Th17 cells. Furthermore, the clinical response to IFN-beta treatment correlated with the induction of IL-27 by IFN-beta in vitro. It is well known that Vitamin D has a number of immunomodulatory effects, and it is used therapeutically to treat psoriasis. Furthermore, low vitamin D levels have been associated with MS and an increased risk of relapse. As part of a clinical trial to assess the effects of vitamin D supplementation in MS, we will be analyzing the effects of vitamin D supplementation on both innate and adaptive immunity.

Projects

  • Title
    • Dysregulation of pathogenic T cells in multiple sclerosis
  • Funding Agency
    • HRB
  • Date From
    • 2006
  • Date To
    • 2009
  • Title
    • The role of CD39+ regulatory T cells in autoimmune disease
  • Funding Agency
    • SFI
  • Date From
    • 2009
  • Date To
    • 2014

Keywords

Autoimmune Diseases (Multiple Sclerosis, Rheumatoid Arthritis); Autoimmunity; IMMUNE FUNCTION; Immune regulation; Immune system; IMMUNE-RESPONSE; IMMUNITY; Immunoassays; IMMUNOLOGICAL MECHANISMS; IMMUNOLOGICAL REGULATION; Immunology; Immunology, Immunotherapy; Immunotherapy; Multiple Sclerosis; MULTIPLE-SCLEROSIS; Regulatory T cells; Rheumatology and rheumatological disorders; T cells; Th17 cells; Tumour Biology/ Immunology

Recognition

Awards and Honours

SFI Starting Investigator Grant (441,000 euro) 2009-2013

HRB postdoctoral fellowship to investigate (226,000 euro) 2006-2009

First prize for the best oral presentation at the Irish Society for Immunology 2008 Annual Congress. 2008

Memberships

British Society for Immunology 2000 – 2010

Irish Society for Immunology 2005 – 2010

Biochemical Society