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Importance of TGF-Beta Signaling in Dendritic Cells to Maintain Immune Tolerance

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Importance of TGF-Beta Signaling in Dendritic Cells to Maintain Immune Tolerance Importance of TGF-beta Signaling in Dendritic Cells to Maintain Immune Tolerance Item Type text; Electronic Dissertation Authors Ramalingam, Rajalakshmy Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 07/10/2021 19:37:27 Link to Item http://hdl.handle.net/10150/228458 IMPORTANCE OF TGF-BETA SIGNALING IN DENDRITIC CELLS TO MAINTAIN IMMUNE TOLERANCE by RAJALAKSHMY RAMALINGAM A Dissertation Submitted to the Faculty of the DEPARTMENT OF IMMUNOBIOLOGY In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 2012 2 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Dissertation Committee, we certify that we have read the dissertation prepared by Rajalakshmy Ramalingam entitled “Importance of TGF-beta Signaling in Dendritic Cells to Maintain Immune Tolerance” and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy Date: 4/16/2012 Pawel Kiela Date: 4/16/2012 Thomas Doetschman Date: 4/16/2012 Fayez Ghishan Date: 4/16/2012 Janko Nikolich Zugich Date: 4/16/2012 David Harris Final approval and acceptance of this dissertation is contingent upon the candidate’s submission of the final copies of the dissertation to the Graduate College. I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requirement. Date: 4/16/2012 Dissertation Director: Thomas Doetschman 3 STATEMENT BY AUTHOR This dissertation has been submitted in partial fulfillment of requirements for an advanced degree at the University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library. Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the author. SIGNED: Rajalakshmy Ramalingam 4 ACKNOWLEDGEMENTS This dissertation would not have been possible without the support and encouragement of my mentors, colleagues and friends. First and foremost, I would like to thank my mentor, Dr. Pawel Kiela, for his guidance, encouragement, support, patience, and most importantly, his friendship during my graduate studies. He has helped me to not only grow as an experimentalist but also as an independent thinker. Thank you Pawel for giving me the opportunity to develop my independence and individuality. I would also like to extend my sincere gratitude to Dr. Ghishan who has always been a source of inspiration for me with his wealth of knowledge and incredible enthusiasm for science. Thank you Dr. Ghishan for all the opportunities that you have given me and for having faith in me. I am extremely grateful to my committee members: Dr. Janko Nikolich Zugich, Dr. Thomas Doetschman and Dr. David Harris for all their support and encouragement. Your insights and comments are very much appreciated. A big thank you to all my lab members (past and present): Monica Kiela, Claire Larmonier, Robert Thurston, Daniel Laubitz, Rita Marie Woodford, Pawel Kojs, Faihza Hill, Hua Xu and Jing Li. I couldn’t have done it without all your help. I would also like to extend my appreciation to Darya Alizadeh, Paula Campbell, Ramireddy Bommireddy and the Genomics shared facility for all their technical help. Special thanks to Collin Lacasse for being a good friend and colleague right from my first day in the United States. Thanks to all the Staff of the Pediatrics and Immunobiology department. A big hug and thanks to my Tucson friends, Neha, Uma and Bhavani for being there for me. I will always cherish our experiences together. Finally, thanks to the Dorrance Family foundation for my fellowship without which this dissertation would not have been possible. 5 DEDICATION I would like to dedicate this dissertation to my husband, parents, brother and grandparents, who have always supported me in all my endeavors, stood by me in all my decisions and loved me unconditionally. Vijay, Amma, Appa, Shiva, Paati’s and Thatha’s I thank you all for loving me and taking care of me. You accepted me for what I am and taught me to become a better person. You gave me strength and showed me that hope remained. You inspired me by your ways, and you showed me that every experience in this life-no matter how bad-serves to teach us a lesson and to give us wisdom. I thank you all for having faith in me and for being there for me. I hope I have given you something to be proud of. Love you all. 6 TABLE OF CONTENTS LIST OF FIGURES ...........................................................................................................8 LIST OF TABLES ...........................................................................................................11 ABBREVIATIONS ..........................................................................................................12 ABSTRACT ......................................................................................................................16 CHAPTER 1 – INTRODUCTION .................................................................................18 1-1 Overall Aims and Objectives .....................................................................20 1-2 Significance of Research .............................................................................21 1-3 Organization of Dissertation ......................................................................22 CHAPTER 2 – LITERATURE REVIEW .....................................................................24 2-1 Immunological Tolerance ...........................................................................24 2-1-1 Mechanisms of Tolerance ..................................................................25 2-1-2 Regulatory T cells and Immune Tolerance .....................................31 2-1-3 Breakdown of Immune Tolerance ....................................................38 2-2 TGFβ – An Essential Mediator of Immune Tolerance ............................39 2-2-1 TGFβ Expression and Activation .....................................................39 2-2-2 TGFβ Receptor and Signaling ..........................................................41 2-2-3 Regulation of Immune responses by TGFβ .....................................42 2-3 Dendritic Cell Mediated Tolerogenic Responses .....................................46 2-3-1 DC Subsets Involved in Tolerance Induction ..................................46 2-3-2 Mechanisms of Tolerance Induction by DCs ..................................50 2-4 Dendritic Cells and TGF-beta....................................................................53 2-4-1 TGFβ Regulation of Langerhans Cell Development ......................53 2-4-2 TGFβ Regulation of DC Maturation and Migration ......................54 2-4-3 TGFβ Regulation of DC Function ....................................................55 2-4-4 Regulation of DC Function by TGFβ in vivo ...................................56 CHAPTER 3 – MATERIALS AND METHODS ..........................................................58 3-1 Mice ..............................................................................................................58 3-2 PCR ..............................................................................................................58 3-3 Generation of BMDCs ................................................................................59 3-4 Flow cytometry ............................................................................................60 3-5 Adoptive transfer of BMDCs in an induced model of colitis ..................62 3-6 Microarray analysis ....................................................................................62 7 TABLE OF CONTENTS - Continued 3-7 Western blot analysis ..................................................................................63 3-8 Realtime PCR ..............................................................................................64 3-9 Histology ......................................................................................................64 3-10 Immunohistochemistry ...............................................................................64 3-11 ELISA and multiplex assays ......................................................................65 3-12 Treg conversion assay .................................................................................66 3-13 iTreg generation ..........................................................................................66 3-14 Statistical analysis .......................................................................................66 CHAPTER 4 – RESULTS ...............................................................................................67 4-1 Specificity of Tgfbr2 deletion in DC-Tgfbr2 KO mice ................................ 67 4-2 Absence of TGFβ signaling in DCs leads to multi-organ autoimmune inflammation ....................................................................................................... 71 4-3 Impaired TGFβ signaling in DCs leads to T and B cell activation
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