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The Role of the Costimulatory TNFR Family Member GITR in T Cell Immunity During an Acute Respiratory Infection

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The Role of the Costimulatory TNFR Family Member GITR in T Cell Immunity During an Acute Respiratory Infection The Role of the Costimulatory TNFR Family Member GITR in T Cell Immunity During an Acute Respiratory Infection by Kuan-Lun Chu A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Immunology University of Toronto © Copyright by Kuan-Lun Chu 2020 Abstract The Role of the Costimulatory TNFR Family Member GITR in T Cell Immunity During an Acute Respiratory Infection. Doctor of Philosophy (2020) Kuan-Lun Chu, Department of Immunology, University of Toronto T cells play a critical role in control of influenza virus, a major human pathogen. Glucocorticoid-induced TNFR-related Protein (GITR), a prosurvival member of the TNFR family, contributes to maximal CD8 T cell responses and protects mice from death upon severe influenza infection. In this thesis, I demonstrate that during influenza infection, GITR ligand (GITRL) is mainly expressed by a group of monocyte-derived tissue infiltrating cells known as inflammatory antigen presenting cells (InfAPC). I show that both GITR and GITRL are detected early in the mediastinal lymph node (mLN) and in the lung tissue when T cells start to accumulate after influenza infection. By detecting phospho-signals downstream of GITR, I show that InfAPC likely provide crucial signals through GITR on T cells in the mLN and afterwards in the lung. This signal is critical for the accumulation of lung effector CD4 and CD8 T cells as well as optimal formation of lung CD4 and CD8 tissue-resident memory T cells (Trm) after influenza infection. The signals that GITR delivers for effector T cell and Trm accumulation most likely occur at the effector phase of the response since GITRL expression is mainly confined to the ii first week of influenza infection. Thus, I investigated how GITR affects effector T cell subpopulations during influenza infection. Ly6C expression defines two effector CD4 T cell subsets while Ly6C and CX3CR1 expression defines three effector CD8 T cell subpopulations. In CD8 T cells, GITR affects the accumulation of all three subsets, with a predominant effect on the least differentiated subset. GITR also selectively upregulates CXCR6 on the less differentiated CX3CR1lo CD8 T cell subsets. GITR affects the accumulation of both CD4 T cell subsets, but selectively upregulates CD127 in the least differentiated CD4 T cell subpopulation which shows a preference for entry into the lung parenchyma. Together, this thesis demonstrates that during influenza infection GITR costimulation in the lung plays an important role in sustaining both highly differentiated effector T cells and Trm precursors, but with differential effects on effector T cell subpopulations. This signal is also critical for optimal formation of lung CD4 and CD8 Trm. iii Acknowledgments I would first like to thank my supervisor, Dr. Tania Watts. Tania, I am so grateful for the support and guidance you provided during my graduate studies. Thank you for allowing me to just walk into your office anytime (even lunch time) to discuss my project. I also want to thank you for letting me purse my research ideas. Some of these ideas were bad ideas that led to nowhere. I would like to thank all the members of the Watts Lab. Ali Abdul-Sater, thank you for providing assistance on molecular biology aspects as well as your computer expertise. Samia Afzal, for answering my random research questions. Nathalia Batista, for hunting free food and free drinks with me. Frank Chang, for making funny jokes that are actually funny. Derek Clouthier, for training me when I first joined the lab. Maria Edilova, for helping me out on that course. Birinder Ghumman, for providing technical assistance and bringing tandoori chicken to lab parties. Melanie Girard, for laughing at my jokes. Jaclyn Law, for listening to my poorly spoken Cantonese. Achire Mbanwi, for the April Fool’s Day joke which I did not fall for. Anh Tran, for telling me where to get good food and bubble tea. Johnny Wang, for making jokes and making strange noise while doing experiments. Angela Zhou, for teaching me lab techniques. I would also like to thank the summer and 4th year undergraduate project students of the Watts Lab: Wenting Gao, Gloria Hou, Ruty Khanolkar, Adam Komorowski, Juliana Lee, Kymberly Litman, Miguel Torres Perez, Kenneth Ting, Rebekah Yuan. I would like to thank my supervisory committee members, Dr. Clinton Robbins and Dr. Jennifer Gommerman, for very helpful comments and discussion during committee meetings. I thank Dionne White and Joanna for flow training and cell sorting. Stacy Nichol and Janice Suarez for taking good care of the animal colony. Carlo Riccardi and Pier Paolo Pandolfi for provision of GITR-/- mice. Ethan Shevach for provision of GITRLexon2fl/fl mice. David Brooks for provision of CD45.1 OT-II mice. I would like to thank my 4th year research project supervisor, Dr. James Carlyle, for giving me the opportunity to do research in his lab as an undergraduate student. As well as my undergraduate project mentor, Tina Kirkham. Tina, I am grateful to have you as my mentor. You not only taught me basic research skills, but also how to deal with failed experiments (technically and emotionally). iv In particular, I would like to thank my parents and my brother for their endless love and support. Especially, when they flew from the other side of the world to Toronto just to celebrate my birthday with me. Last but not least, I would like to thank Minnie Hung for her unconditional love and support during my graduate studies. Minnie, thank you for teaching me all those functions in that word processor which made formatting this thesis a lot easier. v Table of Contents Abstract ............................................................................................................................................ii Acknowledgments .......................................................................................................................... iv Table of Contents ............................................................................................................................ vi List of Tables .................................................................................................................................. xi List of Figures ................................................................................................................................xii List of Publications ........................................................................................................................ xv Abbreviations ................................................................................................................................ xvi Chapter 1 Introduction ..................................................................................................................... 1 1 Introduction ................................................................................................................................. 2 1.1 Influenza virus ..................................................................................................................... 2 1.1.1 Influenza .................................................................................................................. 2 1.1.2 Influenza structure and function .............................................................................. 2 1.1.3 Influenza life cycle .................................................................................................. 4 1.2 Immune responses against influenza virus .......................................................................... 6 1.2.1 Innate immune responses ......................................................................................... 6 1.2.2 APC subsets and priming of T cells ........................................................................ 7 1.2.3 CD8 T cell responses ............................................................................................... 9 1.2.4 CD4 T cell responses ............................................................................................. 10 1.2.5 Central memory and effector memory T cells ....................................................... 11 1.2.6 Tissue resident memory T cells ............................................................................. 11 1.2.7 B cell responses ..................................................................................................... 14 1.3 The TNFR superfamily ...................................................................................................... 16 1.3.1 Classifications and functions of the TNFR superfamily........................................ 16 1.3.2 TNFR signaling ..................................................................................................... 18 vi 1.3.3 TNFRs and viral infections .................................................................................... 21 1.3.4 TNFRs and Trm formation .................................................................................... 23 1.4 GITR and GITRL .............................................................................................................. 26 1.4.1 GITR structure and expression .............................................................................. 26 1.4.2 GITR signaling ...................................................................................................... 28 1.4.3 GITRL structure and expression ............................................................................ 31 1.4.4 GITRL reverse
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