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The Role of ITK in the Development of Gamma Delta NKT Cells: a Dissertation

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The Role of ITK in the Development of Gamma Delta NKT Cells: a Dissertation University of Massachusetts Medical School eScholarship@UMMS GSBS Dissertations and Theses Graduate School of Biomedical Sciences 2012-08-08 The Role of ITK in the Development of Gamma Delta NKT Cells: A Dissertation Catherine C. Yin University of Massachusetts Medical School Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/gsbs_diss Part of the Amino Acids, Peptides, and Proteins Commons, Cells Commons, Enzymes and Coenzymes Commons, Hemic and Immune Systems Commons, Immunology and Infectious Disease Commons, Pharmaceutical Preparations Commons, Therapeutics Commons, and the Tissues Commons Repository Citation Yin CC. (2012). The Role of ITK in the Development of Gamma Delta NKT Cells: A Dissertation. GSBS Dissertations and Theses. https://doi.org/10.13028/mjv4-tw64. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/636 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Dissertations and Theses by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. THE ROLE OF ITK IN THE DEVELOPMENT OF GAMMA DELTA NKT CELLS A Dissertation Presented By Catherine Chih-Tzu Yin Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences, Worcester in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY AUGUST 8th, 2012 IMMUNOLOGY AND VIROLOGY PROGRAM COPYRIGHT INFORMATION The information and data presented in this thesis has appeared in the following publications: Felices, M., C. C. Yin, Y. Kosaka, J. Kang, and L. J. Berg. 2009. Tec kinase Itk in gamma delta T cells is pivotal for controlling IgE production in vivo. Proc. Natl. Acad. Sci. USA 106: 8308–8313. Prince, A. L., C. C. Yin, M. Enos, M. Felices, and L. J. Berg. 2009. The Tec kinases Itk and Rlk regulate conventional versus innate T-cell development. Immunol. Rev. 228: 115–131. Malhotra, N., K. Narayan, O. Cho, K. Sylvia, C.C. Yin, H. Melichar, V. Lefebvre, L.J. Berg, J. Kang. A high mobility group box transcription factor network programs innate IL-17 production. Manuscript submitted ii THE ROLE OF ITK IN THE DEVELOPMENT OF GAMMA DELTA NKT CELLS A Dissertation Presented By CATHERINE CHIH-TZU YIN The signatures of the Dissertation Defense Committee signifies completion and approval as to style and content of the Dissertation Leslie J. Berg, Ph.D, Thesis Advisor Eric Huseby, Ph.D, Member of Committee Liisa Selin, Ph.D, Member of Committee Eva Szomolanyi-Tsuda, Ph.D, Member of Committee Lynn Puddington, Ph.D, Member of Committee The signature of the Chair of the Committee signifies that the written dissertation meets the requirements of the Dissertation Committee Joonsoo Kang, Ph.D, Chair of Committee The signature of the Dean of the Graduate School of Biomedical Sciences signifies that the student has met all graduation requirements of the school. Anthony Carruthers, Ph.D., Dean of the Graduate School of Biomedical Sciences Immunology and Virology Program August 8th, 2012 iii Acknowledgements First and foremost I would like to thank my mentor, Dr. Leslie J. Berg. Through the many years she has guided me through the wonders and frustrations that comes with the world of scientific research. Leslie allowed me the freedom to pursue my own ideas and try out new things but always kindly nudged me back on track when things were not working. She has the gift of calming the nerves, putting up with teeny tiny handwriting and always believing in me when even I doubted myself or when things were not working. Her availability, enthusiasm, patience, wisdom, and ability to explain things in a simple way have helped me through out my research and thesis. I would like to thank the past and present members of the Berg lab, who made lab fun and exciting to come to every day. Thanks to Amanda and John, two people who without I wouldn’t have made it through graduate school; Martin, Yoko, Min, Wenfang and Megan former lab members who set great examples and were always willing to listen to ideas; Regina for always giving advice on things non lab related and for keeping the lab running; Hyun Mu a post-doc who sat next to me and always has good ideas and was always willing to help me with my experiments. I want to thank the rest of the people in the lab including Iivari and Ribhu. In addition I would also like to thank the members of the Kang lab for their friendship, advice and support. iv I would also like to thank 2 people who have been instrumental in getting me through these last few months and have been great friends. I could always call Karen when ever I was stressed no matter what time it was and she always threw great game nights to remind us to have fun outside of lab. I would also like to thank Nang who was my roommate for many years and who I could also rely on to talk to during this stressful time. Many thanks to the pathology department of UMASS Medical School. I would also like to thank my thesis committee, Dr. Joonsoo Kang, Dr. Liisa Selin, and Dr. Eric Husby for their guidance over the past few years along with Dr. Eva Szomolanyi-Tsuda who agreed to be on my committee at the end. In particular, I would like to thank Dr. Joonsoo Kang for his scientific conversations and career advice. Most importantly I would like to thank my family. Without their continued support especially for these past few years I would never have gotten here. I am forever grateful for the support of my parents who have always been supported in my decisions, their encouragement and love. Thanks to my brother, who started graduate school at the same time, for his support and advice. It is to my family that I dedicate this thesis. v Abstract The immune system is a complex network of interacting cells and tissues that is designed to protect the body from pathogens and other foreign substances. T cells are a major component of the immune system and consist of two distinct lineages distinguished by the expression of αβ or γδ T cell receptors (TCR). The Tec family kinase, Itk is an important mediator of signaling downstream of the TCR. Past studies on Itk has focused on how Itk regulates development, activation and differentiation of conventional αβ T cells and more recently how Itk regulates the development of innate-like αβ T cells. However, very little is known about the influence of Itk on γδ T cells. My studies show a previously unknown role for Itk in the development and function of γδ T cells. We report in the absence of Itk, γδ T cells were responsible for the spontaneously -/- elevated levels of serum IgE and Itk mice γδ T cells produced high levels of TH2 cytokines. Furthermore, there was an increase in γδ T cells specifically in the Vγ1.1+Vδ6.3+ (V6) subset that represents the dominant population of γδ NKT cells in Itk-/- mice. In addition, the V6 subset had increased expression of PLZF, a transcription factor normally required for αβ iNKT cell development. We further show that V6 cells develop and mature similar to αβ iNKT cells. Similar to defects previously seen in the terminal differentiation of Itk-/- αβ iNKT cell, V6 cells also had impaired maturation in the thymus in the absence of Itk. This data vi demonstrates a previously unknown role of Itk for the terminal maturation of V6 cells that has been shown to be the cell population that led to spontaneous dermatitis in mice. Given that drug companies have targeted Itk as a potential allergy drug due to Itk’s role in TH2 development and function, our data suggests that further studies on Itk are warranted. vii Table of Contents Approval Page .................................................................................................... iii Acknowledgements ............................................................................................ iv Abstract ............................................................................................................... vi Table of Contents ............................................................................................. viii List of Tables ........................................................................................................ x List of Figures ..................................................................................................... xi Chapter I: Introduction ........................................................................................ 1 Immunoglobulin E-mediated diseases ........................................................... 2 γδ T cells: interface between adaptive and innate immunity ....................... 3 T cell development ........................................................................................... 6 γδ T cell development ...................................................................................... 8 Heterogeneity in selection, function and surface expression within γδ subsets ............................................................................................................ 12 Vγ1.1Vδ6.3 γδ T cell generation and function ............................................. 15 αβ iNKT cells .................................................................................................. 18 TCR signaling ................................................................................................. 22 Tec family kinases ......................................................................................... 26 Tec kinase Itk ................................................................................................
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