University of Groningen Improving stability of human regulatory T cells for clinical purposes He, Xuehui IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2016 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): He, X. (2016). Improving stability of human regulatory T cells for clinical purposes [Nijmegen]: Radboud University Nijmegen Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 30-12-2018
Improving stability of human regulatory T cells for clinical purposes Xuehui He
Thesis: Improving stability of human regulatory T cells for clinical purposes, by Xuehui He The research presented in this thesis was performed at the Department of Laboratory Medicine Laboratory Medical Immunology, Radboud university medical center, Nijmegen, The Netherlanders. ISBN: 978-94-6233-254-6 Cover design:xuehui He and GildePrint Layout: Xuehui He Printed by: Gilderprint Drukkerijen, Enschede www.gildeprint.nl X.H. He, 2016 All right reserved. No parts of this thesis may be reproduced or transmitted, in any form or by any means, without permission of the author.
Improving stability of human regulatory T cells for clinical purposes Proefschrift ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de rector magnificus volgens besluit van het college van decanen in het openbaar te verdedigen op 25 April 2016 om 16:30 uur precies door Xuehui He geboren op 08 november 1978 te Henan (China)
Promotoren Prof. dr. I. Joosten Prof. dr. A.M.H. Boots Copromotoren Dr. J.P.M. Koenen Dr. R.L. Smeets Manuscriptcommissie Prof. dr. L.B. Hilbrands (voorzitter) Prof. dr. G.J. Adema Prof. dr. S.M. van Ham (Universiteit van Amsterdam)
Improving stability of human regulatory T cells for clinical purposes Doctoral Thesis To obtain the degree of doctor from Radboud University Nijmegen on the authority of the Rector Magnificus according to the decision of the Council of Deans to be defended in public on 25 April 2016 at 16:30 hours by Xuehui He born on 08 November 1978 at Henan (China)
Supervisors Prof. dr. I. Joosten Prof. dr. A.M.H. Boots Co-supervisors Dr. H.J.P.M. Koenen Dr. R.L. Smeets Manuscript committee Prof. dr. L.B. Hilbrands (Chairman) Prof. dr. G.J. Adema Prof. dr. S.M. van Ham (University of Amsterdam)
To my beloved family
List of abbreviations APCs CCR CD25 CNIs CNS CsA CTLA-4 DAG DCs EAE FOXP3 GMP GvHD HSCs IBD IL IMPDH IP3 ISDs itreg JAK LAG-3 LAT LcK LFA-1 mabs MHC MMF MPA MS MSCs mtor mtorc1 mtorc2 NFAT antigen presenting cells C C chemokine receptor IL-2 receptor alpha chain calcineurin inhibitors conserved non-coding sequences cyclosporine A CTL-associated protein 4 diacyglycerols dendritic cells experimental autoimmune encephalomyelitis forkhead box protein 3 good manufacturing practice graft-versus-host diseases hematopoietic stem cells inflammatory bowel disease interleukin inosine monophosphate dehydrogenase inositol triphosphate immunosuppressive drugs induced Treg Janus-associated kinase lymphocyte activation gene 3 linker for activation of T cells lymphocyte-specific protein tyrosine kinase lymphocyte function associated antigen 1 monoclonal antibodies major histocompatibility complex mycophenolate mofetil mycophenolic acid multiple sclerosis mesenchymal stromal cells mammalian target of rapamycin. mtor complex 1 mtor complex 2 nuclear factor of activated T cells
NFκB NK ntreg PBMCs PKC PLCγ PMA RA SLE STAT Tconv TCR T FH TGFβ Th TNFR1 TNFR2 TNFα Treg TSDR nuclear factor k chain enhance of activated B cells natural killer cells naturally occurring thymus-derived Treg peripheral blood mononuclear cells protein kinase C phospholipase Cg phorbol myristate acetate rheumatoid arthritis systemic lupus erythematosus signal transducer and activator of transcription conventional T cells T cell receptor follicular helper T cells transforming growth factor β T helper type I receptor for tumour necrosis factor alpha type II receptor for tumour necrosis factor alpha tumour necrosis factor alpha regulatory T cells Treg specific demethylated region
Table of Contents Chapter 1 General introduction............................... 13 Chapter 2 Molecular pathway profiling of T lymphocyte signal transduction pathways; Th1 and Th2 genomic fingerprints are defined by TCR and CD28-mediated signalling. 51 Chapter 3 Mycophenolic acid-mediated suppression of human CD4+ T cells: more than mere guanine nucleotide deprivation...................... 81 Chapter 4 Single CD28 stimulation induces stable and polyclonal expansion of human regulatory T cells............................... 103 Chapter 5 TNFR2-agonist facilitates high purity expansion of human Treg starting from low purity isolated Treg.............................. 125 Chapter 6 Targeting PKC in human T cells using sotrastaurin (AEB071) preserves regulatory T cells and prevents IL-17 production..................... 151 Chapter 7 Lymphocyte isolation from human skin for phenotypic analysis and ex vivo cell culture..................................... 173 Chapter 8 Summary and Discussion........................... 189 Chapter 9 Nederlandsesamenvatting........................... 207 Chapter 10 Acknowledgement............................... 213 List of Publications.............................. 216 Curriculum Vitae................................ 218