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I the Role of SHP-1 in Regulating the T Cell Response to Suppression By i The role of SHP-1 in regulating the T cell response to suppression by regulatory T cells Emily Rose Mercadante Succasunna, NJ M.S., University of Virginia, 2012 B.S., Ursinus College, 2010 A Dissertation presented to the Graduate Faculty of the University of Virginia in Candidacy for the Degree of Doctor of Philosophy Department of Microbiology, Immunology, and Cancer Biology University of Virginia June 2017 ii ABSTRACT The balance between activation of T cells and their suppression by regulatory T cells (Treg) is dysregulated in autoimmune diseases and cancer. In the past decade, evidence has accumulated to suggest that autoimmune diseases not only feature defective Tregs, but also feature T cells that are resistant to suppression by Tregs. On the other hand, in cancer, T cells are unable to mount anti-tumor responses due to the Treg- enriched suppressive microenvironment. Much remains unknown about what regulates this interplay between T cells and Tregs. However, it has become clear that maintaining the tenuous balance between T cell activation and suppression by Tregs is essential for immune homeostasis and prevention of disease. In this work, we investigated the role of the protein tyrosine phosphatase SHP-1, in regulating T cell responses to T cell receptor (TCR) stimulation. SHP-1 has been defined as a negative regulator of TCR signaling based on studies in global SHP-1 knockout mice and immortalized cell lines. We expanded in-depth upon these findings by utilizing two mouse models in which SHP-1 is deleted specifically in T cells and a pharmacological inhibitor of SHP-1. With this approach, we show that SHP-1 limits the responsiveness of T cells to TCR stimulation in a cell-intrinsic manner. Furthermore, we identified a novel function of SHP-1 in regulating the susceptibility of T cells to Treg- mediated suppression. Thus, SHP-1 deficiency rendered naïve CD4+ and CD8+ T cells resistant to Treg-mediated suppression in vitro, and regulated in vivo CD4+ T cell susceptibility to Treg suppression under conditions of homeostatic expansion. Mechanistically, SHP-1-deficient T cells did not mediate resistance to Treg suppression via soluble factors in vitro. We specifically ruled out an influence of IL-4 iii signaling on Treg-resistance in SHP-1-deficient T cells, as previous work had shown that SHP-1-deficient T cells are hyper-sensitive to IL-4 and that IL-4 can induce wildtype T cells to resist suppression. Rather, SHP-1 controlled the activation of the PI3K/Akt pathway, the enhancement of which has been previously linked to the induction of T cell resistance to Treg suppression. Collectively, these data establish SHP-1 as a critical player in setting the threshold downstream of TCR signaling and identify a novel function of SHP-1 as a regulator of T cell susceptibility to Treg-mediated suppression in vitro and in vivo. Thus, SHP-1 and the PI3K/Akt pathway could represent potential immunotherapeutic targets to modulate susceptibility of T cells to Treg suppression. In addition to investigating the role of SHP-1 in T cells, we also preliminarily assessed the regulatory function of SHP-1 in Tregs. Previous work from our lab established that Tregs from global knockout SHP-1 mice were more suppressive than wildtype Tregs. Thus, we generated a mouse model in which SHP-1 is deleted specifically in Tregs to assess the Treg cell-intrinsic function of SHP-1. Preliminary results herein recapitulate the inhibitory role of SHP-1 on Treg function. Thus, SHP-1- deficient Tregs were more potently suppressive than wildtype Tregs. The dual role of SHP-1 in T cells and Tregs provides the possibility of inhibiting SHP-1 in Tregs for treatment of autoimmune disease, and inhibiting SHP-1 in T cells to boost anti-tumor responses. Overall, this work better informs immunotherapeutic strategies for autoimmune disease and cancer, and highlights the importance of targeted approaches to avoid counterproductive systemic effects. iv Acknowledgements I would like to express my gratitude to the many individuals who have provided support throughout the completion of my thesis work. First, I would like to thank my mentor, Dr. Ulrike Lorenz, for allowing me the opportunity to undertake this work and for her scientific insight and advice throughout. I would also like to thank my thesis committee members, Drs. Loren Erickson, Kenneth Tung, Kodi Ravichandran, Vic Engelhard, and Tim Bender for challenging me to think more critically and pushing me to become an expert in my work. I thank the administrative staff of the CIC, especially Peggy Morris and Michelle Butler, who always offered a friendly smile and answers to my questions. I also thank Sandy Weirich for her hard work keeping MIC students on track. Thank you to my friends in the Erickson lab: William Loo, Tim Rosean, Kelly Cox, Christine Coquery, Nekeithia Wade, and Fionna Surette, with whom I shared many frustrations, inspirations, and good conversations. I was so very fortunate to have Jessica Harakal as a lab neighbor. Jessica could be counted on for scientific help, a good laugh, or a hug. I was also lucky to find another Jersey Girl and best friend in Brittany Durgin. I am grateful to all my many friends here- Glen Hirsh, Tim Raines, Jon and Kasia Handing, Sowmya Narayanan, Monica Buckley, Katie Margulieux, Caitlin Naylor, Dylan and Natalie Kennedy, Amber Woods, and Jason True. And thank you to my friend Kari Duck, for her long-distance commiseration while we both completed our doctorates. My dog, April, whom I adopted four years ago, and whose love is too large to contain in one sentence, made sure I did not take things too seriously during my doctoral v work. Most importantly, words cannot express my gratitude for my parents’ support, without which I would not have succeeded in this process. My parents have always had faith in me and allowed me the space to find my own path and pursue my dreams, no matter how challenging. I dedicate this work to them, and their infinite patience and love. vi Table of Contents Title ……………………………………………………………………………...page i Abstract ………………………………………………………………………….page ii Acknowledgements ……………………………………………………………...page iv Table of Contents ………………………………………………………………...page vi List of Abbreviations …………………………………………………………….page vii List of Tables and Figures ………………………………………………………page xiii Chapter 1: Introduction ………………………………………………………….page 1 Chapter 2: Materials and Methods ………………………………………………page 42 Chapter 3: T cells deficient in the tyrosine phosphatase SHP-1 resist suppression by regulatory T cells ………………………………………………………………. page 53 Chapter 4: Additional models of SHP-1 deficiency in T cells: Studies in motheaten and CD4-Cre SHP-1f/f mice, and pharmacological inhibition of SHP-1 via sodium stibogluconate ……………………………………………………………………page 92 f/f f/f Chapter 5: SHP-1-deficient Tregs from dLck-Cre SHP-1 mice and Foxp3-Cre SHP-1 mice are more suppressive than wildtype Tregs …………………………………page 114 Chapter 6: Conclusions, Future Directions, and Significance …………………...page 122 References ………………………………………………………………………..page 151 Appendix A – Review Article ……………………………………………………page 181 vii List of Abbreviations 4-1BB Tumor necrosis factor receptor superfamily member 9 αCD3 anti-CD3 Ab Antibody(s) ACT Adoptive cell transfer Ag Antigen(s) Akt Protein kinase B ANOVA Analysis of variance AP-1 Activator protein 1 APC Antigen-presenting cell(s) BL6 C57BL/6 cAMP cyclic adenosine monophosphate CAR-T Chimeric antigen receptor T cell Casp-3 Caspase-3 Cbl-b/c-Cbl Casitas-B-lineage-lymphoma proteins CFSE Carboxyfluorescein succinimidyl ester CTL(s) Cytotoxic T lymphocyte(s) CTLA-4 Cytotoxic T-lymphocyte-associated protein 4 viii DC(s) Dendritic cell(s) dLck Distal promoter of Lck DN Double negative (CD4-CD8-) thymocyte DP Double positive (CD4+CD8+) thymocyte EAE Experimentally-induced autoimmune encephalomyelitis ELISA Enzyme-linked immunosorbent assay Erk Extracellular-regulated kinases FMO Fluorescence minus one Foxp3 Forkhead box P3 GITR Glucocorticoid-induced TNFR-related protein GVHD Graft-versus-host disease HCV Hepatitis C virus HIV Human immunodeficiency virus HLA Human leukocyte antigen HSV Herpes simplex virus IBD Inflammatory bowel disease ICAM-1 Intracellular adhesion molecule 1 IDO Indoleamine 2,3-dioxygenase ix IFNγ Interferon gamma IL Interleukin i.p. Intraperitoneal i.v. Intravenous IPEX Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome ITAM(s) Immune tyrosine-based activation motif(s) Jak Janus kinase proteins JIA Juvenile idiopathic arthritis KD Knockdown KO Knockout LAG3 Lymphocyte-activation gene 3 LAT Linker for activation of T cells Lck Lymphocyte-specific protein tyrosine kinase LFA-1 Lymphocyte function-associated antigen 1 LN Lymph node(s) MACS Magnetic activated cell sorting me/me motheaten mice x MFI Mean fluorescence intensity MHC I/II Major histocompatibility complex class I or class II mRNA Messenger ribonucleic acid MS Multiple sclerosis mTOR Mechanistic (formerly mammalian) target of rapamycin mut Mutant Nedd4 Neural precursor cell expressed developmentally downregulated protein 4 NFAT Nuclear factor of activated T-cells NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells OVA Ovalbumin OX40 Tumor necrosis factor receptor superfamily member 4 p85 Regulatory subunit of PI3K pAkt phosphorylated Akt PBS Phosphate-buffered saline pDC(s) Plasmacytoid dendritic cell(s) PI3K Phosphoinositide 3-kinase PKCθ Protein kinase C theta PMA Phorbol 12-myristate 13-acetate xi pMHC peptide: Major histocompatibility complex PTEN Phosphatase and
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