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CD4+ T Cell Production of IL-10 and Regulation of Immune Responses in Aging

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CD4+ T Cell Production of IL-10 and Regulation of Immune Responses in Aging CD4+ T cell production of IL-10 and regulation of immune responses in aging A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of Doctor of Philosophy Immunology Graduate Program, College of Medicine 2018 by Maha Almanan M.D., Faculty of Medicine, University of Khartoum, Khartoum, Sudan Committee Chair: David Hildeman, Ph.D. Abstract The immune system plays a vital role in the protection against invading pathogens. A successful immune response is dictated by the fine balance between pro- and anti- inflammatory mediators. With age the immune system undergoes a progressive dysregulation due to the dramatic reduction in the naïve T cell pool, a relative clonal expansion of memory T cells as well as accumulation of regulatory T cells. Another aspect of this immune dysregulation is the persistent, low grade inflammation that develops with age and is referred to as (inflammaging). Together, dysfunctional immune responses and inflammaging are a great risk for serious age-related pathologies. Thus, understanding the mechanisms regulating this age-related immune dysfunction is critical for healthy aging. Viral infections including latent cytomegalovirus (CMV) are thought to be one of driving forces of age-related alterations in immune function and inflammaging. While T cell responses are critical against CMV infection, the regulatory mechanisms that control latency are not well understood. Regulatory T cells are known to accumulate with age, likely due to their enhanced survival. While Treg accumulated with age, their per cell functionality remains controversial and possibly model dependent. Treg cells are important regulators of acute infections (including CMV). However, the impact of Treg on latent CMV is unclear. In chapter 3 we aimed at investigating the role of Foxp3+ regulatory T cells (Treg) in latent murine cytomegalovirus (MCMV) infection. We show that Treg played divergent roles in the control of MCMV infection. In the spleen, Treg antagonize CD8+ T cell effector function and promote viral persistence, while in the II salivary gland Treg prevent IL-10 production from Foxp3- CD4+ T cells and limit viral reactivation and replication. Together, work in chapter 3 broadens our understanding of the homeostasis and functions of regulatory T cells and IL-10 with age. Our discovery that Treg control IL-10 during latent CMV infection was intriguing. IL-10 is a known regulatory cytokine, playing a major role in shaping immune responses and regulating excessive inflammation. Thus, IL-10 may contribute to counter-regulation of age-driven inflammation. In chapter 4 of this dissertation, we aimed to investigate the role of IL-10 with age and further understand the cellular and molecular mechanisms underlying its production. We provide evidence that aging favors the accrual of CD4+ Foxp3- IL-10+ T cells. Additionally, T follicular helper cells (Tfh) were major producers of IL-10 in aged humans and mice which we have designated as Tfh10 cells. Interestingly, both IL-21 and IL-6 were indispensable for the accumulation of Tfh10 cells with age. Finally, the loss of BCL6 in Foxp3- CD4+ T cells enhanced the production of IL-10 with age. Results from this study highlight the dynamic regulatory/counter-regulatory balance controlling age-related inflammation. More importantly, we show that despite age-driven intrinsic defects in adaptive immune responses, blockade of IL-10 signaling is largely sufficient to restore germinal center (GC) B cell responses in aged mice. Together work from chapter 3 and 4 underscores the complexity of the unique age-related regulatory networks that shape immune responses to latent infections, as well as vaccines. III IV Acknowledgments I would like to express my sincere gratitude to my mentor, Dr. David Hildeman. Thank you for your endless support and patience over the last five years, sense of humor, immense scientific knowledge and for challenging me to think independently. Thank you for believing in me at times when I didn't believe in myself, I cannot think of a better mentor to have. I don’t know how you do it, but I always looked up to you and I aspire to become a great role model and pass on what you've taught me to my own students one day. I just want you to know that I am a much better scientist because of you and for that I will always be grateful for the rest of my life. I would like to acknowledge members of my committee who provided endless support and guidance throughout my PhD study. Dr. Claire Chougnet, I am grateful for all the invaluable scientific discussions which has greatly impacted my PhD training and I am also thankful for the time you have taken to offer career and life advice. Dr. Kasper Hoebe, you have always challenged my scientific curiosity and for that I thank you. Dr. Kris Steinbrecher, thank you for investing your time and personally assisting with my experiments. Dr. Rhonda Cardin, thank you for your patience while introducing me to the world of virology and assisting with experiments, I am truly grateful for all your support. I would like to thank my lab members Allyson Sholl, Jana Raynor, Kun-Po Li, Matthew Alder and Pulak Tripathi, who have grown to become my second family. You all were very helpful at various times at the beginning of me joining the lab and I have continued to succeed because of it. Cyd Castro, Sarah Jones, Rachel Walters, and Sharmilia V Shanmuganad, thank you all for your contributions to my work at different times. Especially within the last 2 years, we have grown to become one sisterhood in science and I am forever grateful. I would also like to thank the Immunology Program who accepted me and gave me one of the best opportunities of my life and allowed me to meet some of the most wonderful people and some of my best friends. I especially thank Hesham Shihata, Kate Carroll, Carolyn Rydyznski, and Courtney Jackson, for always caring, listening and being a shoulder to lean on throughout the years. Lastly, I would like to thank my family for their continued love and support, especially my mother who was my biggest motivation to pursue my graduate studies. Even though you are no longer in the present, I hope that I have made you proud. Dad, you have taught me to continue to keep my head up and gave me your blessings and because of the way you have raised me, I feel I have become a better parent. To my children, Yasmeen and Mosaab, at times it was tough to juggle being a student and being your mother. At times people have asked how do I manage, I just say to myself because of you. I am truly blessed to have you in my life. VI Table Of Contents Abstract ....................II Acknowledgments ....................V Table of Contents ....................VII List of Abbreviations ....................X Chapter 1: Introduction ....................1 1. Age-dependent immune dysregulation .....................1 1.1. Defects in innate immune-responses with age ....................2 1.2. Defects in adaptive immune-responses with age ....................6 1.2.1. B cells ...................6 1.2.2. T cells ....................8 (i) Homeostatic defects in T cells with age .....................8 (ii) Functional defects in T cells with age ....................9 1.3. Aging and its impact on vaccine responsiveness ....................10 2. Regulatory T cells ....................11 2.1. Thymus derived Treg (tTreg) ....................12 2.2. Peripherally derived Treg (pTreg) ...................12 2.3. Treg functionality and specialization .......................14 2.4. Treg in aging ....................15 3. Cytomegalovirus (CMV) 16 3.1. Acute CMV ....................17 3.2. Latent CMV ....................20 3.2.1. Cellular and molecular mechanisms controlling CMV reactivation from latency ....................21 3.2.2. CMV in aging ....................22 3.2.3. Regulatory mechanisms controlling CMV ...................23 VII (i) Treg in CMV ....................23 (ii)IL-10 in CMV ...................24 4. Interleukin-10 (IL-10) ...................25 4.1. Transcriptional regulation of IL-10 production in CD4 T cells ..................26 4.1.1. TCR mediated IL-10 expression ..................26 4.1.2. Cytokine mediated IL-10 expression ....................27 4.2. IL-10/IL-10R and signaling pathway ...................29 4.3. Biological effects of IL-10 ........................31 4.4. Aging and IL-10 .....................33 5. T follicular helper (Tfh) cells .....................34 5.1. Aging and Tfh cells ...................35 6. Interleukin-6 (IL-6) .......................37 6.1. IL-6 signaling pathway ..........................37 6.1.1. Classical pathway ............................37 6.1.2. Trans-signaling pathway ...........................38 6.2. Biological effects of IL-6 .............................39 6.3. Aging and IL-6 .........................................40 7. Interleukin-21 (IL-21) ........................................41 7.1. IL-21 signaling pathway ................................41 7.2. Biological effects of IL-21 ..............................42 7.3. Aging and IL-21 .............................43 Summary ......................................44 References ...................................46 Chapter 2: T-reg Homeostasis and Functions in Ageing ................................81 VIII References .................................97 Chapter 3: Tissue-specific control of latent CMV reactivation by regulatory T cells ...................................104 References ..............................126
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