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Innate Lymphoid Cells: Transcriptional Profiles and Cytokine Developmental Requirements Michelle Lauren Robinette Washington University in St

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Innate Lymphoid Cells: Transcriptional Profiles and Cytokine Developmental Requirements Michelle Lauren Robinette Washington University in St Washington University in St. Louis Washington University Open Scholarship Arts & Sciences Electronic Theses and Dissertations Arts & Sciences Spring 5-15-2018 Innate Lymphoid Cells: Transcriptional Profiles and Cytokine Developmental Requirements Michelle Lauren Robinette Washington University in St. Louis Follow this and additional works at: https://openscholarship.wustl.edu/art_sci_etds Part of the Allergy and Immunology Commons, Immunology and Infectious Disease Commons, and the Medical Immunology Commons Recommended Citation Robinette, Michelle Lauren, "Innate Lymphoid Cells: Transcriptional Profiles and Cytokine Developmental Requirements" (2018). Arts & Sciences Electronic Theses and Dissertations. 1571. https://openscholarship.wustl.edu/art_sci_etds/1571 This Dissertation is brought to you for free and open access by the Arts & Sciences at Washington University Open Scholarship. It has been accepted for inclusion in Arts & Sciences Electronic Theses and Dissertations by an authorized administrator of Washington University Open Scholarship. For more information, please contact [email protected]. WASHINGTON UNIVERSITY IN ST. LOUIS Division of Biology and Biomedical Sciences Immunology Dissertation Examination Committee: Marco Colonna, Chair Maxim Artyomov Takeshi Egawa Gwen Randolph Wayne Yokoyama Innate Lymphoid Cells: Transcriptional Profiles and Cytokine Developmental Requirements by Michelle Lauren Robinette A dissertation presented to The Graduate School of Washington University in partial fulfillment of the requirements for the degree of Doctor of Philosophy May 2018 St. Louis, Missouri © 2018, Michelle L. Robinette ii Table of Contents List of Figures………………….………………….………………….……………………...iv List of Abbreviations………………….………………….………………….……………….v Acknowledgments………………….………………….………………….………………...vii Abstract………………….………………….………………….……………………………xi CHAPTER 1: Introduction………………….………………….………………….………1 1.1 Innate and Adaptive Immunity in Lymphocytes…………….………………….……..2 1.2 ILCs: The New Kids on the Block…………….………………….…………………...6 1.3 Cytotoxicity…………….………………….………………….……………………...10 1.4 Module 1: Intracellular Pathogens and Viruses…………….………………….…….13 1.5 Module 2: Barrier Maintenance and Helminths…………….………………….…….15 1.6 Module 3: Extracellular Bacteria and Fungi….…………….………………….…….16 1.7 γc Cytokines and Lymphoid Development…………….………………….………….19 1.8 Perspectives…………….………………….……………….……………….………..21 CHAPTER 2: Transcriptional Programs Define Molecular Characteristics of ILC Subsets and Classes………………….………………….………………….…….………………...22 2.1 Abstract…………….………………….………………….……………….…………..23 2.2 PART 1: Mouse ILC Transcriptional Profiles …………….………………………...24 2.2.1 Introduction …………….…………..….………………………………………..24 2.2.2 Materials and Methods …………….…………..….…………………………… 26 2.2.3 Results …………….…………..….……………………………………………..31 2.2.4 Discussion …………….…………..….…………………………………………43 2.2.5 Figures …………….…………..….……………………………………………..46 2.3 PART 2: Human ILC Transcriptional Profiles …………….………………………..64 2.3.1 Introduction …………….…………..….………………………………………..64 2.3.2 Materials and Methods …………….…………..….…………………………… 66 2.3.3 Results …………….…………..….……………………………………………..68 2.3.4 Discussion.…………….…………..….…………………………………………73 2.3.5 Figures …………….…………..….……………………………………………..76 CHAPTER 3: Jak3 Deficiency Blocks ILC Development While Pharmacologic Inhibition Impairs Function ………………….………………….………………….…….………….84 3.1 Abstract…………….………………….………………….……………….…………85 3.2 Introduction…………….………………….………………….……………….……..86 ii 3.3 Materials and Methods…..…………….………………….……………….…………88 3.4 Results…..…………….………………….……………….………………………….91 3.5 Discussion………….………………….……………….…………………………….99 3.6 Figures…..…………….………………….……………….………………………...102 CHAPTER 4: IL-15 Sustains IL-7R-Independent ILC2 and ILC3 Development …..113 4.1 Abstract…………….………………….………………….……………….………..114 4.2 Introduction…………….………………….………………….……………….……115 4.3 Materials and Methods…..…………….………………….……………….………..117 4.4 Results…..…………….………………….……………….………………………...119 4.5 Discussion………….………………….……………….…………………………...126 4.6 Figures…..…………….………………….……………….………………………...131 CHAPTER 5: Concluding Remarks ………………….………………….……………..141 5.1 Brief Summary of Findings…………….………………….………………………..142 5.2 Modular Immunity Revisited…………….………………….………………………144 5.3 ILCs and Gamma Chain Cytokines …………….………………….……………….146 5.4 Innate and Adaptive Immunity in Lymphocytes Revisited …………….…………..148 5.5 Future Directions …………….……………………………………………………..149 References ………………….………………….………………….………………………151 APPENDIX 1: Transcriptional Analysis Extended Data ………………….………….164 1A Unique Transcripts of ILC Subsets…………….………………….………………..165 1B Spectrum of Shared Transcriptional Profiles Between siLP ILCs…………….……168 1C ILC3-Specific Transcriptional Programs…………….……………………………..174 1D ILC1 and NK cell Transcriptional Programs in Tissues…………….………………182 1E Transcripts Differentially Expressed Between NK cells and ILC1 …………….…...187 1F Generation of a Core ILC Signature …………….…………………………………..192 1G ILC3 Subset-Specific Transcriptional Signatures …………….…………………….195 APPENDIX 2: Wolverine Whole Exome Sequencing Results………………….……...198 CV………………….………………….………………….………………………………..205 iii List of Figures Figure 1: Sorting Strategy for Mouse ILC……………….………………………………….46 Figure 2: Mouse ILC Frequency Among Lymphocytes………………….…………………48 Figure 3: Mouse ILC Diversity.………………….………………….……………………....49 Figure 4: Unique Transcripts of Individual ILC Subsets..…………….………………….…50 Figure 5: Small Intestine Lamina Propria Gene Signature..…………….…………………..52 Figure 6: TFs, Cytokines, and Chemokines Expressed by ILCs..……….………………….53 Figure 7: Spectrum of Shared Transcriptional Profiles Between siLP ILCs………………..54 Figure 8: ILC3-Specific Transcriptional Programs and Cell Surface Markers ………….....55 Figure 9: Transcripts Differentially Expressed Between NK cells and ILC1………………57 Figure 10: Generation of a Core ILC Signature Distinct from NK Cells..…………….……59 Figure 11: ILCs lack TCRδ protein but express TCR-γ transcripts...……………………….60 Figure 12: ILCs Express CXCR6 at Higher Levels Than NK cells ………………………..62 Figure 13: IEL ILC1 Have Intermediate Characteristics Between ILC1 and NK cells ……63 Figure 14: Human ILCs Cluster Separately from Adaptive T cell Counterparts…..……….76 Figure 15: Tonsillar Subsets Cluster Separately from Circulating Blood NK cells ………..77 Figure 16: ILCs are Transcriptional Distinct from T helper cells…………………………..79 Figure 17: Unique and Overlapping Transcriptional Profiles Between ILCs and T helper Cells.…………….………………….………………….…………………………………...80 Figure 18: Pathway Analysis of Differentially Expressed ILC Transcripts…………………82 Figure 19: Identification of the Wolverine Phenotype ….………………………………….102 Figure 20: ILCs Fail to Develop in the Wolverine Mice.…………….…………………….103 Figure 21: Wolverine Mice Have Impaired Lymphocyte Generation……………………...104 Figure 22: Wolverine Mice Have Increased Myeloid Generation….……………………....105 Figure 23: Wolverine Lymphocyte Deficiency is Cell-Intrinsic …………….…………….106 Figure 24: Identification of Frameshift Mutations in the Nr1d1tm1Ven/LacZ Mouse Line.…107 Figure 25: Jak32067insC Causes the Wolverine Phenotype……………………….……….….108 Figure 26: Jak3 Deficiency Progressively Reduces Restricted Lymphoid Progenitors……110 Figure 27: JAK3 Inhibition Impairs Human ILC Cytokine Production…………….……...111 Figure 28: JAK3 Inhibition Impairs Human ILC Cytokine Production…………….……...112 –/– + Figure 29: Il7ra Mice Have Residual ILCs in siLP, Skewed to CCR6 ILC3…………...131 Figure 30: ILC2s are Not Substantially Preserved in Colon or Lung…………….………..132 –/– – Figure 31: Residual Il7ra ILC2 are Predominantly ST2 …………….…………………..133 + Figure 32: ST2 ILC2 Produce More Cytokines After Stimulation…………….………….134 –/– Figure 33: Il7ra ILC3s Produce IL-22 Normally…………….………………….……….136 –/– Figure 34: Il7ra ILC3s Partially Protect Mice from C. rodentium Infection…………….137 + Figure 35: CCR6 ILC3 are Transcriptionally Distinct…………….………………….…...138 + Figure 36: CCR6 ILC3 Highly Express Bcl-2, Enhanced by Lack of IL-7R……………...139 –/– –/– –/– Figure 37: Il7ra Il15 Mice Generate Significantly Fewer ILCs than Il7ra Mice……..140 iv List of Abbreviations AHR Aryl hydrocarbon receptor αLP Alpha-lymphoid progenitor AR Autosomal recessive BCR B cell receptor BMDM Bone marrow derived macrophages CHILP Common helper ILC precursor CLP Common lymphoid progenitor cNK (cell) Conventional natural killer cell DD Death domain DN Double Negative DTT Dithiothreitol EAE Experimental Autoimmune Encephalomyelitis EDTA Ethylenediaminetetraacetic acid EILP Early innate lymphoid progenitor Eomes Eomesodermin FasL Fas ligand γc IL-2rg common gamma chain HCT Hematopoeitic cell transplant IEL Intraepithelial lymphocyte IFN-γ Interferon gamma iILC1 Intraepithelial ILC1 ILC Innate lymphoid cell ILC1 Innate lymphoid cell group 1 ILC2 Innate lymphoid cell group 2 ILC2P Innate lymphoid cell group 2 precursor ILC3 Innate lymphoid cell group 3 ILCP Innate lymphoid cell precursor ILL Innate-like lymphocyte ImmGen Immunological Genome Consortium Indel Insertion/Deletion iNK immature NK IL- Interleukin- LP Lamina propria LTi (cell) Lymphoid tissue inducer cell LTin (cell) Lymphoid tissue initiator cell LTα1β2 Lymphotoxin α1β2 MAC Membrane attack complex MAIT (cell) Mucosal-associated invariant T cell MHC Major Histocompatiblitiy Complex MHC I Major Histocompatiblitiy Complex Class I MHC II Major Histocompatiblitiy Complex Class II v MZ Marginal zone NK (cell) Natural Killer cell NKT (cell) Natural Killer T cell PID Primary Immuodeficiency pre-NKP pre-NK precursor RA Rheumatoid
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