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Regulation of Cd4 T Cell Responses to Il-7 by Ifn-Alpha and Tgf-Beta in Treated Hiv Disease

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Regulation of Cd4 T Cell Responses to Il-7 by Ifn-Alpha and Tgf-Beta in Treated Hiv Disease REGULATION OF CD4 T CELL RESPONSES TO IL-7 BY IFN-ALPHA AND TGF-BETA IN TREATED HIV DISEASE By: THAO NGUYEN Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Advisor: Scott F. Sieg, PhD Department of Pathology Immunology Training Program CASE WESTERN RESERVE UNIVERSITY JANUARY 2017 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES THAO P NGUYEN Candidate for the degree of Doctor of Philosophy* Committee Chair CLIFFORD HARDING, MD/PhD Committee Member SCOTT SIEG, PhD Committee Member MICHAEL LEDERMAN, MD Committee Member DONALD ANTHONY, MD/PhD Committee Member JOHN TILTON, MD Committee Member CLIVE HAMLIN, PhD Date of Defense November 21, 2016 *We also certify that written approval has been obtained for any proprietary material contained therein. ii I dedicate this dissertation to my sister and late mother. iii Table of contents Page Dedication iii Table of contents iv List of figures and tables viii Acknowledgements x List of abbreviations xi Abstract 1 Chapter 1: Introduction 2 HIV pathogenesis 2 CD4 T cell count recovery in HIV infection following ART initiation 9 Homeostatic proliferation in response to interleukin-7 is a mediator of T cell 10 recovery The role of IFN-I in treated HIV infection 14 The anti-viral and anti-proliferative functions of IFN-I 14 TGF-β and additional cytokines that may contribute to low CD4 T cell count 17 recovery in treated HIV infected patients Chapter 2: Interferon-α inhibits CD4 T cells proliferation and signaling in 19 response to IL-7 and IL-2 Abstract 19 Introduction 19 Methods 21 Cells and cell culture Flow cytometry Statistical analyses iv Results 24 IFN-α impairs IL-7-induced proliferation responses and diminishes 24 cellular function in CD4+ T cells IFN-α diminishes T cell viability 29 IFN-α inhibits P-Akt but not P-STAT5 in IL-7-treated cells 31 IFN-α inhibits P-Akt signaling that is induced by IL-2 but not by SDF-1 33 Inhibition of P-Akt or P-STAT5 blocks cellular proliferation and 35 function Discussion 37 Chapter 3: Diminished CD4 T cell responsiveness to IL-7 in immune 42 failure subjects is related to diminished CD127 expression and increased IFN-α expression Abstract 42 Introduction 43 Methods 45 Patients Peripheral blood mononuclear cell and T-cell isolation mRNA analyses Stimulation conditions Flow cytometry Statistical analyses Results 48 IL-7 mediated proliferation and induction of CD25 are diminished in 48 CD4+ T cells from immune failure patients CD4+ T cells from immune failure patients exhibit decreased CD127 53 expression and increased immune activation v Interferon-stimulated gene and IFN-α mRNA expression are increased in 53 CD3+T cells from immune failure patients Diminished IL-7 responsiveness in immune failure patients is related to 55 expression of CD127 and IFN-α IFN-α responsiveness is not diminished in CD4+ T cells from immune failure 57 patients Discussion 59 Chapter 4: TGF-β inhibits IL-7 induced proliferation in memory but not 64 naive CD4 T cells Abstract 64 Introduction 64 Methods 67 Peripheral blood mononuclear cell and CD4 T cell subset isolation Stimulation conditions Flow cytometry Statistical analyses Results 69 TGF-β inhibits memory but not naive CD4 T cell proliferation in response 69 to IL-7 TGF-β suppresses IL-7 mediated induction of c-myc expression in naive 72 and memory CD4 T cells TGF-β does not inhibit IL-7 receptor signaling in memory CD4 T cells 74 and enhances S6 kinase signaling in naive CD4 T cells GSK-3 inactivation partially overcomes TGF-β-mediated inhibition of 75 IL-7-induced proliferation and c-myc induction in memory CD4 T cells Discussion 78 Chapter 5: Discussion and future directions 71 vi Diminished responsiveness to IL-7 may contribute to poor 81 = CD4 T cell count recovery in treated HIV infection The role of IFN-I in poor CD4 T cell count recovery in treated 84 HIV infection TGF-β selectively inhibits memory CD4 T cell proliferation in response to 86 IL-7 IFN-α and TGF-β utilize different mechanisms to inhibit IL-7-induced 87 proliferation in CD4 T cells Literature cited 89 vii List of Tables and Figures Page Table 1. Clinical characteristics and immune phenotypes of subjects 46 Figure 1.1 CD4 T cell loss and viral load in HIV infection 2 Figure 1.2 Proposed contributors to HIV-associated immune activation 6 Figure 1.3. HIV life cycle showing sites of action of different classes of 8 antiretroviral drug Figure 1.4 CD4 T cell recovery is highly variable and related to nadir 10 CD4 T cell count Figure 1.5 IL-7 receptor signaling promotes cell survival and drives proliferation 11 Figure 2.1. IFN inhibits IL-7-induced proliferation 25 Figure 2.2. The magnitude of IFN-α mediated inhibition of IL-7 induced 26 proliferation is dose dependent Figure 2.3 Pre-incubation of CD4+ T cells in IFN-α plus IL-7 reduces 27 T cell function compared with pre-incubation of cells in IL-7 alone Figure 2.4 Gating strategy to assess viability 29 Figure 2.5 IFN-α causes cell death, primarily in nondividing T cells, 30 in IL-7-treated cell cultures Figure 2.6 IFN-α impairs P-Akt but not P-STAT5 signaling in IL-7-treated cells 31 Figure 2.7 Impaired responses to IL-2 but not SDF-1 in CD4 cells exposed 34 to IFN-α Figure 2.8 Inhibition of PI3K or STAT5 reduced cell proliferation, decreased 35 functionality, and enhanced cell death in cells treated with IL-7. Figure 3.1 CD4+ T-cell responses to IL-7 are diminished in immune failure 49 patients Figure 3.2 CD4- T cell proliferation in response to IL-7 is diminished in IF 51 subjects Fig. 3.3 Induction of P-STAT5 and P-Akt in response to IL-7 52 Fig. 3.4 T cells from immune failure patients exhibit increased expression of 53 viii interferon stimulated genes and IFN-α Fig. 3.5 IL-7 induced CD25 expression is related to expression of CD127 55 Fig. 3.6 CD4+ T- cell responses to IFN-α were not diminished in immune 57 failure patients. Fig. 3.7 IFN-α mediated induction of cell death in CD4 T cell subsets 59 Figure 4.1 TGF-β differentially affects naive and memory CD4 T cell 69 proliferation in response to IL-7 Figure 4.2 TGF-β inhibits IL-7 induced % divided and proliferation index 71 in memory CD4 T cells Figure 4.3 TGF-β inhibits IL-7 mediated induction of c-myc expression 72 in naive and memory CD4 T cells Figure 4.4 TGF-β does not inhibit IL-7 receptor signaling in memory 74 CD4 T cells and enhances S6 phosphorylation in naïve CD4 T cells Figure 4.5 TGF-β mediated inhibition of IL-7 induced proliferation and 76 c-myc expression in memory CD4 T cells is reversed by the inactivation of GSK-3 Figure 5.1 Differential mechanisms of inhibition of IL-7 induced 88 proliferation by TGF-β and IFN-α ix Acknowledgements I would like to thank my PI, Dr. Scott Sieg. During my time at Case, Scott provided a wonderful learning environment that allowed me develop as a scientist. He is encouraging, genuine, thoughtful and a great role model for me. I would also like to thank Dr. Michael Lederman for his guidance and feedback. I find Michael exceptional because his actions demonstrate his dedication to helping others develop their projects and careers on top of his various responsibilities. I would like to thank Dr. Clifford Harding, Dr. Donald Anthony and Dr. John (Chip) Tilton for their guidance and help over the years while serving on my thesis committee. Dr. Harding has done an excellent job in his role as the chair of my committee by always being clear and organized. I appreciate Dr. Don Anthony and Dr. John Tilton for their guidance in helping me think about my project as well as my career goals. Finally, I would like to thank my collaborators and the members of the Sieg and Lederman labs. I want to thank Dr. Supriya Shukla and Dr. Robert Asaad for their contribution to my immune failure project. I would like to thank Doug Bazdar for teaching me various laboratory techniques as well as always being available to help me in the lab. Overall, the contributions from all the mentioned people have resulted in a pleasant experience in my journey to obtaining my degree. x List of Abbreviations AIDS -acquired immune deficiency syndrome ART-antiretroviral therapy CMV- Cytomegalovirus CH-CHIR-99021 c-myc- myelocytomatosis EBV- Epstein–Barr virus GSK-3-glycogen synthase kinase 3 HC-healthy control HIV-human immunodeficiency virus IFI16-gamma interferon inducible protein 16 IgA-immunoglobulin A IL-1β- interleukin-1beta IL-2-interleukin-2 IL-6-interleukin-6 IL-7-interleukin-7 IL-10- interleukin 10 IF-immune failure IS-immune success IP-10-gamma interferon inducible protein 10 IRF-7- interferon regulatory factor 7 IRF-9- interferon regulatory factor 9 ISG-interferon stimulated genes xi ISGF-3- interferon stimulated gene factor-3 ISRE- IFN stimulatory response elements LAV-lymphadenopathy-associated virus LN-lymph node Mx-myxovirus OAS- 2’, 5’-oligoadenylate synthetase PBMCs-peripheral blood mononuclear cells pDCs-plasmacytoid dendritic cells PKR-protein kinase R SCID- severe combined immunodeficiency SDF-1-stromal derived factor 1 SEB- Staphylococcal Enterotoxin B STAT5- signal transducer and activator of transcription 5 TCR-t cell receptor TGF-β- transforming growth factor-beta TLR-toll like receptor TRECs- T cell rearrangement excision circles TYK2-tyrosine kinase 2 xii The Regulation of Response to IL-7 by IFN-alpha and TGF-beta in Treated HIV Disease Abstract by THAO NGUYEN Antiretroviral therapy administration has nearly eliminated acquired immune deficiency syndrome (AIDS) -related mortality in human immunodeficiency virus (HIV) infected patients.
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