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The Role of Tumor Suppressors, SHIP and Rb, in Immune Suppressive Cells Michelle Marie Collazo Ruiz University of South Florida, [email protected]

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The Role of Tumor Suppressors, SHIP and Rb, in Immune Suppressive Cells Michelle Marie Collazo Ruiz University of South Florida, Collazo.Davis@Gmail.Com University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School January 2012 The Role of Tumor Suppressors, SHIP and Rb, in Immune Suppressive Cells Michelle Marie Collazo Ruiz University of South Florida, [email protected] Follow this and additional works at: http://scholarcommons.usf.edu/etd Part of the American Studies Commons, Cell Biology Commons, Immunology and Infectious Disease Commons, and the Molecular Biology Commons Scholar Commons Citation Collazo Ruiz, Michelle Marie, "The Role of Tumor Suppressors, SHIP and Rb, in Immune Suppressive Cells" (2012). Graduate Theses and Dissertations. http://scholarcommons.usf.edu/etd/4016 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. The Role of Tumor Suppressors, SHIP and Rb, in Immune Suppressive Cells by Michelle M. Collazo Ruiz A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Cell Biology, Microbiology and Molecular Biology College of Arts and Sciences University of South Florida Co-Major Professor: Dmitry Gabrilovich, M.D., Ph.D. Co-Major Professor: William Kerr, Ph.D. Eduardo Sotomayor, M.D., Ph.D. Mark Alexandrow, Ph.D. Gary Reuther, Ph.D. Augusto Ochoa, M.D. Date of Approval: January 26th, 2012 Keywords: myeloid-derived suppressor cells (MDSC), regulatory T cells (Tregs), cancer, allogeneic immune responses, differentiation, granulocytic MDSC, monocytic MDSC, Retinoblastoma gene (Rb1), SHIP1 Copyright © 2012, Michelle M Collazo Ruiz DEDICATION I dedicate this work… To my parents… I have been blessed with wonderful and supportive parents, Maria E. Chanlatte Ruiz and Ramon Collazo Gonzalez and their equally wonderful and supportive partners Luis M. Chanlatte and Rosaura Rios Padilla, respectively. Thank you for always believing in me and trusting the choices I have made. I love and appreciate you so much. To Ronald Lincoln Davis, my husband… We began our relationship while I was in graduate school and since then, you have been my champion, always empowering me to keep going while providing unconditional love and support in anything that I do. Your huge listening of me has kept me present to who I am and why I am doing this, even when I didn’t want to be. Your words “babe, be easy on yourself” have been invaluable. To my future children… Being a scientist and earning my PhD was a dream, now a dream fulfilled. I continue to dream and know myself as someone capable of fulfilling on those dreams. During this time, my husband, Ronald L. Davis, moved to New York City to live his dream of training as a dancer. Again, a dream fulfilled. I want my kids to know that they can dream big and fulfill on these dreams. It isn’t easy but it is a life worth living. ACKNOWLEDGEMENT Many people have contributed to me and this work in immeasurable ways. I acknowledge everyone who has been willing to hear my story, be inspired by it, challenge it, and/or add to it. This has given life to my work. Many of you have been with me at different points throughout this journey as a graduate student, with its many victories and rough spots. You ALL, in one way or another, have so willingly provided me with so much guidance, knowledge, encouragement, and importantly unconditional love and support. I thank God for having you in my life. To my family, Ronald L. Davis, Maria Chanlatte Ruiz, Ramon Collazo, Luis Chanlatte, Rosaura Rios Padilla, Francisco Collazo, Valerie Collazo, Ramon Collazo Jr., and the rest of the Collazo, Ruiz and Davis family, I acknowledge and love you dearly. The foundation, love and support you provide make everything in my life possible. I am so proud to be a part of this beautiful family. To my close friends and fellow labmates, Nicole Fortenbery, Myrnali Ortiz, Brianna Lenox and Kim Paraiso, I acknowledge you. You wonderful women made me really look forward to coming into the lab even when my experiments weren’t working. Thank you for always being willing to listen to me and to share your life with me. Special thanks to you, Nicole, for showing me what is possible in friendship. You have been like a soul mate. Words cannot describe the extent of my gratitude. To my mentors, Dr. William Kerr, Dr. Dmitry Gabrilovich, and respective lab members, I acknowledge you. I really don’t think I could have gotten better research training than I did with you two very exceptional principal investigators and the brilliant researchers working for you. I greatly admire and appreciate all of you. To the Cancer Biology PhD Program, students, faculty and coordinator, Cathy Gaffney, I acknowledge you. I am very proud and honored to be a part of this exclusive program which includes only outstanding and innovative researchers willing to do great science. To my committee members, Eduardo Sotomayor, MD; Gary Reuther, PhD; Mark Alexandrow PhD; and Augusto Ochoa, MD; I acknowledge you. Thank you for always challenging me and demanding the best from me while demonstrating great respect, support and partnership. To Landmark Education, I acknowledge you. The training and development I received from Landmark programs is invaluable. I got and keep getting that even though life (and research) does not always turn out perfect, as planned, I can still be powerful and live a life that I love, by design. To the salsa dancing community in Tampa, the Florida Army National Guard and old high school friends from Dorado Academy, I acknowledge you. These are other important communities which I have had the privilege to be a part of while being a grad student. They have enriched my life greatly, making it very wholesome, fun and comforting. Last but not least, to Kim, Bob and Buddy Thompson, I acknowledge you. You opened your home to me for what was first going to be just 6 months to what became a little over a year and surely, a lifetime to follow. You guys have made so much possible in my life, beyond a place to stay to simply finish my PhD work. Your daily contribution, from conversation, to inspiration, to love, to wholesome healthy food, to entertainment, among many other things, has been invaluable. Thank you for creating with me and letting me be part of a Fun and Empowering Community that Works for All. TABLE OF CONTENTS LIST OF FIGURES ………………………………………………………………………. iv ABSTRACT ……………………………………………………………………………….. vi Chapter 1. Background …………………………………………………………………… 1 Regulation of Immune Responses ……………………………………………… 1 Immunological Tolerance ……………………………………………….. 2 Immune Surveillance and Immunoediting …………………………….. 4 Immune Cells that Suppress Immune Responses …………………..………... 7 Regulatory T cells (Tregs) ………………………………………………. 7 Discovery of Tregs ……………………………………………… 7 Development of Tregs …………………………………………. 9 Suppressive Mechanisms of Tregs …………………………... 14 Tregs in Pathological Conditions and Clinical Implications .. 18 Myeloid Derived Suppressor Cells (MDSC) ………………………….. 23 Discovery of MDSC …………………………………………….. 23 Development of MDSC ………………………………………... 25 Heterogeneity of MDSC ……………………………………….. 30 Suppressive Mechanisms of MDSC ………………………….. 33 MDSC in Pathological Conditions and Clinical Implications .. 37 The Role of Tumor Suppressor, SHIP, in Regulating the Immune System .. 39 Discovery of SHIP ……………………………………………………..... 39 SHIP Structure and Functional Domains ……………………………… 39 SH2 Domain ……………..………………………………………. 40 5’ Inositol Phosphatase ..………………………………………. 40 NPXY and PxxP Motifs ..…………………………………….... 42 Factors that Dictate SHIP Signaling ………………………………..…. 42 Murine Models of SHIP-Deficiency ………………………………..….. 44 SHIP and the Hematopoietic Compartment ……………………..…… 46 SHIP in T Cells ……………………………………………..……. 46 SHIP in Myeloid Cells ……………………………………..……. 48 The Role of Tumor Suppressor, Rb, in Regulating the Immune System ..… 49 Discovery of Rb ……………………………………………………..…… 49 Rb Structure and Functional Domains …………………………..……. 51 Regulation of Rb Expression and Activation …………………..…….. 53 Rb Signaling Pathways …………………………………………..……… 55 Rb and the Cell Cycle …………………………………..………. 55 Rb and Differentiation ………………………………..………… 58 Rb and Apoptosis …………………………………..………….. 61 Rb and DNA Repair ………………………………..……………. 62 Murine Models of Rb Deficiency ………………………..…………….. 64 Rb and the Hematopoietic Compartment ……………..……………… 66 i Chapter 2. Materials and Methods ……………………………………..………………. 71 Mice ………………………………………………………………..………………. 71 Conditional Deletion of SHIP or Rb1 ………………………..…………………. 72 Cell Purification ………………………………………………..…………………. 72 Flow Cytometry ………………………………………………..…………………. 73 In Vitro Culture ………………………………………………..………………….. 74 BrdU Incorporation ……………………………………………………………….. 74 Mixed Leukocyte Reaction ………………………………………………………. 75 Western Blotting ………………………………………………………………….. 75 Quantitative Real-Time PCR (qRT-PCR) ……………………………………… 77 Chromatin Immunoprecipitation ………………………………………………… 77 G-CSF Neutralization and SDF-1 ELISA ………………………………………. 79 Adoptive Transfer of T cells for Colitis and GvHD Induction ………………... 80 Clinical and Histologic Examination of Colitis ………………………………… 80 Vascularized Heart Rejection Model …………………………………………… 81 Statistics …………………………………………………………………………… 82 Chapter 3. SHIP Limits Immunoregulatory Capacity in the T-cell Compartment … 83 Introduction ……………………………………………………………………….. 83 Results …………………………………………………………………………….. 85 Mice with Germline SHIP-Deficiency have Increased Numbers of Conventional
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