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Developmental Control of Innate Lymphoid Cells

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Developmental Control of Innate Lymphoid Cells DEVELOPMENTAL CONTROL OF INNATE LYMPHOID CELLS By Theresa L. Geiger A Dissertation Presented to the Faculty of the Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy New York, NY May 2016 __________________ __________________ Joseph Sun, PhD Date Dissertation Mentor Copyright © by Theresa Lynn Geiger 2016 Dedication To my family, for all of their love and support “A loveless world is a dead world, and always there comes an hour when one is weary of prisons, of one's work, and of devotion to duty, and all one craves for is a loved face, the warmth and wonder of a loving heart.” - Albert Camus, The Plague - iii Abstract Innate lymphoid cells (ILCs) are a recently defined lineage of cells derived from the common lymphoid progenitor (CLP). They are primarily found at barrier surfaces such as the intestine and skin, and have established roles in homeostasis and protection from pathogens at these sites through their production of cytokines. The founding member of the ILC lineage, natural killer (NK) cells, can also rapidly kill infected or transformed cells. Here, we report on two different players in the complex network of transcription factors and cytokines that govern ILC development: the transcription factor Nfil3 and the cytokine TGF- β. We show that the transcription factor Nfil3 is not only required for the development of NK cells, but also all other ILC lineages. Nfil3-deficient mice lack all ILC subsets, including NK cells, and are severely deficient in an early ILC progenitor. Nfil3-deficient mice are also drastically more susceptible to intestinal pathogens such as C. rodentium and C. difficile, likely due to their lack of intestinal ILCs. Suprisingly, Nfil3-/- mice are only slightly more susceptible to chemically induced colitis and are less susceptible to a carcinogen-induced model of colorectal cancer, indicating ILCs may also play a pathogenic role in certain settings. Furthermore, we show that the cytokine TGF-β is dispensable for normal NK cell development. Deletion of TGF-β signaling in NK cells at the NK progenitor (NKP) stage has no observed affect on NK cell development. However, TGF-β insensitive NK cells appear to have a defect in expansion and persistence after viral infection, indicating that TGF-β may play a role in determining effector and memory NK cell fates. These findings have increased iv our understanding of the complex network of signals governing ILC development. In particular, our identification of Nfil3 as a transcription factor necessary for both NK cell and ILC development helps establish the relationship between these two lineages during early lymphoid development. v Acknowledgements First of all, I would like to thank my thesis mentor, Joe Sun. Thank you for being so supportive and excited about science. I have really enjoyed my time in the lab. Thank you also to all of the current and former Sun lab members: Carolyn Zawislak, Matt Firth, Jenny Karo, Sharline Madera, Aimee Beaulieu, Lexus Johnson, Clair Geary, Tim O’Sullivan, Moritz Rapp, Nick Adams, and Orrel Weizman. You have all been great to work with. Special thanks to Aimee, Jenny, and Sharline, for your great advice about life as well as lab. I would also like to thank our collaborators on the Nfil3 project: Alan Hanash, Marcel van den Brink, Maggie O’Connor, Mike Abt, Eric Pamer, Georg Gasteiger, Andrew Dannenberg, and David Montrose. The project would not have been possible without your advice and expertise. Thank you also to Pooja Khanna, a rotation student who worked with me on the TGF-β project. Thank you to my thesis committee, Ming Li, Jedd Wolchok, and Eric Pamer, for your support, advice, and insight. Thank you also to my external examiner, David Artis, and my exam chair, Alexander Rudensky. Thank you to the rest of the Sloan Kettering and Weill Cornell immunology departments, especially the Rudensky and van den Brink labs, for your help and advice. Thank you to Kathy Hsu, Jeanette Boudreau, and the rest of NK club for your insightful questions and suggestions. Thank you to the National Institutes of Health, National Institute of Allergy and Infectious Disease, and the Starr Cancer Consortium for their funding support. I would also like to thank my undergraduate research mentors, Dinesh vi Rao and David Baltimore, for giving me my first opportunity to pursue biology research. Thank you to all of the Gerstner Sloan Kettering Graduate School. It has been a wonderful, enriching experience and I am so glad I chose to attend GSK. Thank you to Ken Marians, GSK dean, for leading this fantastic graduate school program. Thank you to Linda Burnley, associate dean, for all of your support. Thank you to the GSK administrative staff who keep the school running: Ivan Gerena, Katherine Gentile, Iwona Abramek, and Maria Torres. Maria, thank you for being GSK’s go-to problem solver. Iwona, thank you for all of your help with the dissertation and defense process. Thank you also to the other GSK students, especially my classmates. I look forward to watching all of you do great things in the years to come. Thank you so much to my family and friends for your neverending love and support. To my mother, thank you for reminding me that no time spent learning is ever wasted. To my father, thank you for always encouraging me to pursue my dreams. To Christian, thank you for always being there for me. To Hannah, thank you for your advice and support. To my IMSA and Caltech friends, thank you for being so excited and passionate about learning and achieving new things. To my fiancé, Rob, thank you for letting me drag you out of sunny California to live in crazy New York City for five years. Thank you for all of your love, support, and encouragement. Thank you for agreeing to get a dog. To my dog, Steven, thank you for always being happy to see me. To everyone else who has supported me before or during graduate school, thank you. vii Table of Contents List of Figures ...................................................................................................... xii List of Abbreviations ............................................................................................ xv Chapter 1: Introduction .......................................................................................... 1 I. Development of Innate Lymphoid Cells .......................................................... 1 1. ILC Precursors ............................................................................................ 2 2. Differentiation of ILC1 and NK cells ........................................................... 3 3. Differentiation of ILC2 ................................................................................. 5 4. Differentiation of ILC3 and LTi Cells ........................................................... 6 II. Development and Maturation of Natural Killer Cells1 ................................... 12 1. Stages of NK Cell Development and Differentiation1 ............................... 13 2. Transcriptional Control of Early NK Cell Development1 ........................... 15 3. Transcription Factors Governing NK Cell Maturation1 .............................. 18 4. Regulation of Effector NK Cell Responses and Memory Formation1 ....... 20 III. ILCs in Disease and Homeostasis .............................................................. 26 1. NK cells and ILC1 ..................................................................................... 26 2. ILC2 .......................................................................................................... 27 3. ILC3 and LTi Cells .................................................................................... 28 IV. Summary .................................................................................................... 30 Chapter 2: Nfil3 is Crucial for the Development of all Innate Lymphoid Cells ..... 33 I. Introduction ................................................................................................... 33 1. The Transcription Factor Nfil3/E4BP4 ...................................................... 33 2. Nfil3 in the Immune System ..................................................................... 34 viii II. Results ......................................................................................................... 36 1. Intestinal Group 3 ILCs are Severely Reduced in Nfil3-deficient Mice2 .... 36 2. Cell-intrinsic Requirement for Nfil3 in ILC3 Development2 ....................... 37 3. Nfil3 is Essential for Resistance Against Intestinal Pathogens2 ............... 37 4. Development of the ILC Precursor Depends on Nfil32 ............................. 40 5. Nfil3-independent Maintenance of Mature NKp46+ ILC3s2 ...................... 41 6. ILC2 Populations are Severely Diminished in Nfil3-deficient Mice2 .......... 41 7. Nfil3-/- and WT Mice Develop Similar Levels of Colitis After DSS Treatment ..................................................................................................... 43 8. Nfil3-/- Mice are Less Susceptible to AOM/DSS Polyp Formation ............ 44 III. Discussion ................................................................................................... 60 IV. Materials and Methods ............................................................................... 63 1. Mice2 ......................................................................................................... 63 2.
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