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Bacterial Exposure and Immune Homeostasis: A BACTERIAL EXPOSURE AND IMMUNE HOMEOSTASIS: A MECHANISTIC VIEW OF THE HYGIENE HYPOTHESIS By JENNY LYNN JOHNSON Submitted in fulfillment of the requirements for the Degree of Doctor of Philosophy Thesis Advisor: Dr. Brian A. Cobb, Ph.D. Department of Pathology CASE WESTERN RESERVE UNIVERSITY May 2015 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of Jenny Lynn Johnson Candidate for the degree of Doctor of Philosophy* Committee Chair Eric Pearlman Committee Member George Dubyak Committee Member Kristie Ross Committee Member Brian Cobb Committee Member Clive Hamlin Date of Defense March 16, 2015 *We also certify that written approval has been obtained for any proprietary material contained therein 2 Dedication I would like to dedicate this work to those who have supported me through the six years I have spent at CWRU, and in particular my parents, Mark and Sharon Johnson, and my cousins, Janice, David and Henry Graves. 3 Table of Contents List of Tables .................................................................................................................................... 7 List of Figures ................................................................................................................................... 8 Acknowledgements........................................................................................................................ 10 List of Abbreviations ...................................................................................................................... 12 Abstract .......................................................................................................................................... 15 Chapter 1: An Introduction to Bacteroides fragilis, PSA, and Asthma ........................................... 17 1.1 Hygiene Hypothesis ............................................................................................................. 18 1.2 Intro to Asthma .................................................................................................................... 21 1.3 Currently available therapeutics .......................................................................................... 22 1.4 Intro to Bacteroides fragilis ................................................................................................. 24 1.5 Polysaccharide A .................................................................................................................. 25 1.6: Immunomodulation by Bacteroides fragilis and Polysaccharide A .................................... 26 Chapter 2: Clonal T cell Expansion Induced by PSA Treatment ..................................................... 28 2.1: Summary ............................................................................................................................. 29 2.2: Introduction ........................................................................................................................ 30 2.3: Methods .............................................................................................................................. 31 2.3.1: Mice and Bacteria ........................................................................................................ 31 2.3.2: Airway Inflammation Model ........................................................................................ 31 2.3.3: T cell Flow Cytometry................................................................................................... 32 2.3.4: Histology ...................................................................................................................... 32 4 2.3.5: Deep Sequencing ......................................................................................................... 33 2.3.6: General Data Analyses ................................................................................................. 33 2.4: Results ................................................................................................................................. 33 2.4.1: Phenotypic Description of PSA Responding T cells ...................................................... 33 2.4.2: Analysis of TCR from PSA responding T cells via Deep Sequencing ............................. 34 2.4.3: Clonal T cell Expansion by PSA ..................................................................................... 36 2.4.4: Asthma Induction is Inhibited by PSA-expanded T Cells.............................................. 39 Chapter 3: Polysaccharide A from Bacteroides fragilis Inhibits Asthma Induction ....................... 42 3.1: Summary ............................................................................................................................. 43 3.2: Introduction ........................................................................................................................ 44 3.3: Methods .............................................................................................................................. 46 3.3.1: Mice and bacteria ........................................................................................................ 46 3.3.2: Asthma models ............................................................................................................ 46 3.3.3: Sterile T cell sorting ...................................................................................................... 47 3.3.4: Histology ...................................................................................................................... 47 3.3.5: General data analysis ................................................................................................... 48 3.4: Results ................................................................................................................................. 48 3.4.1: Oral PSA exposure protects against OVA-induced airway inflammation .................... 48 3.4.2: CD4+ T cells drive PSA-mediated asthma protection ................................................... 51 3.4.3: PSA responding T cells are not traditional Foxp3+ regulatory T cells .......................... 55 5 3.4.4: PSA mediated asthma inhibition is IL-10 dependent ................................................... 56 Chapter 4: Novel T cell-T cell Interaction Promotes Immune Homeostasis .................................. 58 4.1: Summary ............................................................................................................................. 59 4.2: Introduction ........................................................................................................................ 59 4.3: Methods .............................................................................................................................. 61 4.3.1: Mice and Bacteria ........................................................................................................ 61 4.3.2: Asthma model .............................................................................................................. 61 4.3.3: Sterile T cell sorting ...................................................................................................... 62 4.3.4: Cell Culture ................................................................................................................... 62 4.3.5: Histology ...................................................................................................................... 62 4.3.6: Flow analysis ................................................................................................................ 63 4.3.6: General data analysis ................................................................................................... 63 4.4: Results ................................................................................................................................. 63 4.4.1: Suppressive IL-10 Production is External to PSA Experienced T cells .......................... 63 4.4.2: PSA Experienced T cells induce IL-10 Production in Foxp3+ T cells .............................. 64 4.4.3: A Soluble Molecule Mediates Effector Memory T cell-Regulatory T cell Interaction .. 68 4.4.4: Soluble Mediator from Activated TEM Cells Induces IL-10 Production in vivo ............. 69 4.4.5: Activated TEM cells Inhibit Asthma Induction ............................................................... 70 Chapter 5: Discussion and Future Directions ................................................................................. 72 6 List of Tables Chapter 3: Clonal T cell Expansion Induced by PSA Treatment Table 1: Sequencing information generated through next generation sequencing...35 Table 2: Compilation of TCRβ CDR3 zwitterionic sequences......................................40 7 List of Figures Chapter 2: Clonal T cell Expansion Induced by PSA Treatment Figure 1: PSA immunization promotes an anti-inflammatory phenotype in CD4+ T cells.............................................................................................................................34 Figure 2: Vβ and J segment usage does not vary with PSA immunization..................36 Figure 3: CDR3 loop length remains consistent with PSA immunization....................37 Figure 4: PSA immunization induces clonal proliferation of CD4+ T cells....................38 Figure 5: PSA and OVA clonally expand CD4+ T cells with a similar sequence frequency....................................................................................................................39
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