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I a STUDY of the MECHANISM by WHICH CD86 REGULATES Igg1

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I a STUDY of the MECHANISM by WHICH CD86 REGULATES Igg1 A STUDY OF THE MECHANISM BY WHICH CD86 REGULATES IgG1 DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Nicholas W. Kin, B.S. ***** The Ohio State University 2007 Dissertation Committee: Approved by Professor Virginia M. Sanders, Advisor Professor William Lafuse ____________________________________ Professor Denis Guttridge Advisor Integrated Biomedical Science Graduate Program Professor Susheela Tridandapani i i ABSTRACT The goal of this dissertation was to determine the molecular mechanism by which CD86 (B7-2) stimulation on a CD40 ligand (CD40L)/Interleukin-4 (IL-4)-activated B cell activates NF-κB and increases the level of IgG1 produced. Our laboratory reported previously that stimulation of CD86 on a CD40L/IL-4-activated B cell increases the amount of IgG1 produced on a per cell basis, without affecting class switch recombination (CSR) or mRNA stability. In addition, CD86 stimulation increases the expression and binding of the transcription factor Oct-2 to the 3’-IgH enhancer. The CD86-induced increase in Oct-2 expression is associated with increased activation and nuclear localization of NF-κB, specifically the p50/p65 subunits. Since NF-κB is involved in numerous biological responses, therapeutic interventions aimed at either suppressing or enhancing antibody production via CD86 signaling would need to target the specific intermediates activated by CD86 upstream of NF-κB activation. Thus, the hypothesis tested in this dissertation is that stimulation of CD86 on a CD40L/IL-4- activated B cell activates a distinct signaling pathway within the B cell to increase the activation of NF-κB and the gene transcription mediated by the 3’-IgH enhancer. The present data are the first to show the CD86 signal transduction pathway in a B cell proximal to the activation of NF-κB and the regulation of gene activity. We show that ii CD86 stimulation on a CD40L/IL-4-activated B cell increased the activity of PI3K, as well as the phosphorylation state of PDK1, Akt, IKKα/β, PLCγ2, and PKCαβ, to increase gene activity mediated by NF-κB and the hs4 region of the 3’-IgH enhancer. The present data also show that addition of CD28/Ig to CD40L/IL-4-activated B cells on Wt, but not CD86- or CD19-deficient, B cells increased the level of phosphorylation of Lyn and CD19, as well as the amount of Lyn, Vav, and PI3K proteins that immunoprecipitated with CD19. In vivo, serum IgG1 levels following immunization with a T cell-dependent antigen were decreased in mice receiving Wt-T/CD86-deficient B cells when compared to mice receiving Wt-T/Wt-B cells. The decrease in serum IgG1 was associated with a decrease in the level of B cell-associated Oct-2 mRNA and protein, but a normal level of germline IgG1 mRNA and Th2 cell-dependent IL-4. The significance of this dissertation is that it is the first study to identify the mechanism by which CD86 induces an intracellular signaling pathway directly in the B cell. The knowledge gained from this work will not only provide a molecular mechanism by which CD86 stimulation regulates the level of an IgG1 response, but also identify potential molecular targets for therapeutic interventions to selectively regulate the level of an IgG1 response positively or negatively. iii ACKNOWLEDGMENTS I am forever grateful to my mentor Dr. Virginia Sanders for all her guidance and support during my graduate training in her laboratory. She taught me how to think and ask questions like a scientist. Her commitment to teaching and dedication to her students was an inspiration to always strive to become a better scientist. She also created an excellent working environment in which I was able to ask and test novel scientific questions. I also want to thank my committee members at The Ohio State University, Drs. Denis Guttridge, William Lafuse, and Susheela Tridandapani for their guidance and helpful discussion during meetings. I am also thankful to the Integrated Biomedical Science Graduate Program with Dr. Alan Yates as Director for creating an environment that fosters good science and the pursuit of excellence. In addition, I thank everyone in the Integrated Biomedical Science Graduate Program office that helped me through the first few years of graduate school and all the paperwork associated with it. I would also like to acknowledge both past and present members of the Sanders laboratory. Drs. Deborah Kasprowicz, Adam Kohm, and Joseph Podojil were instrumental in laying the groundwork for my dissertation research. Dr. Joseph Podojil also helped to develop my early technical skills in the laboratory. I would also like to iv thank our laboratory manager, Scot Erbe, for his help and dedication to keeping the lab running. Finally, I would also like to thank the current members of laboratory, Kurt Lucin, Jackie McAlees, and Alan Smith. I am forever grateful to my parents Wayne and Denise. It was through their guidance and examples that I became the person I am today. They instilled a combination of their values, work ethic, love, pursuit of education, and a never say die attitude that helped me to achieve the goals that I set for myself. Finally, I would like to thank my wife Amanda, who has always been there for me through the successes and the failures of this dissertation work. I will be forever grateful for her love and support throughout graduate school. v VITA August 23, 1979 . Born – Findlay, Ohio 2001 . B.S. Biochemistry, Bowling Green State University. 2002. Graduate Research Associate The Ohio State University. 2003 – 2006. Integrated Immunobiology Training Grant Fellowship The Ohio State University. 2006 – 2007. Graduate Research Associate The Ohio State University. PUBLICATIONS Research Publications 1. Fisher, I.B., Kin, N.W., McAlees, J.W., Sanders, V.M. Regulation of Adaptive Immunity by the Neurotransmitter Norepinephrine. Current Immunol Reviews 2006 Nov;2(4):361-70. 2. Kin, N.W. and Sanders, V.M. CD86 stimulation on a B cell activates the PI3K/Akt and PLCγ2/PKCα/β signaling pathways. J Immunol. 2006 Jun 1;176(11):6727- 35. 3. Kin, N.W. and Sanders, V.M. It takes nerve to tell T and B cells what to do. J Leukoc Biol. 2006 Jun;79(6):1093-104. 4. Podojil, J.P., Kin, N.W., Sanders, V.M. CD86 and beta2-adrenergic receptor signaling pathways, respectively, increase Oct-2 and OCA-B Expression and binding to the 3'-IgH enhancer in B cells. J. Biol. Chem. 2004 May 28;279(22):23394-404. vi FIELDS OF STUDY Major Field: Integrated Biomedical Science vii TABLE OF CONTENTS ABSTRACT………………………………………………………………………………ii ACKNOWLEDGMENTS………………………………………………………………..iv VITA……………………………………………………………………………………...vi LIST OF FIGURES……………………………………………………………………...xii LIST OF ABBREVIATIONS……………………………………………………………xv CHAPTERS 1. INTRODUCTION AND LITERATURE REVIEW……………………………...1 1.1 Divisions of the immune system……………………………………………..1 1.1.1 Innate immune system……………………………………………..1 1.1.2 Adaptive immune system……………………………………….….3 1.2 Effector cell populations of the acquired immune system…………………...4 1.2.1 B cell development………………………………………………...4 1.2.2 B cells and germinal centers……………………………………….6 1.2.3 B cell differentiation into an antibody-secreting cell………………8 1.3 CD40 and IL-4 receptor stimulation on a B cell……………………………10 1.3.1 IL-4 receptor stimulation on a B cell……………………………..10 1.3.2 CD40 stimulation on a B cell……………………………………..14 1.4 Cognate B and T cell interaction……………………………………………16 1.4.1 B cell expression of CD86 and costimulation of a T cell………...16 1.4.2 CD86 direct signaling to a B cell…………………………………17 1.5 Regulation of IgG1 production……………………………………………...19 1.5.1 Regulation of the IgH locus and the 3’-IgH enhancer………..…..19 1.5.2 Regulation of Oct-2 expression and transcriptional activity……...21 viii 1.6 Conclusion and hypothesis………………………………………………….22 2. MATERIALS AND METHODS………………………………………………..28 2.1 Animals……………………………………………………………………..28 2.2 Cell lines…………………………………………………………………….28 2.3 Resting B cell isolation and culture…………………………………………29 2.4 In vivo cell transfer and immunization……………………………………...30 2.5 Western blot………………………………………………………………...30 2.6 Immunoprecipitation (IP)…………………………………………………...31 2.7 Flow cytometry……………………………………………………………..31 2.8 PI3-Kinase enzyme-linked immunoassay (ELISA)………………………...32 2.9 Quantitative real-time polymerase chain reaction (PCR)…………………...32 2.10 IgG1 enzyme-linked immunoassay (ELISA)………………………………33 2.11 Chromatin immunoprecipitation (ChIP)…………………………………..34 2.12 Transient transfections…………………………………………………….35 2.13 Transfection isolation and reporter gene assay……………………………36 2.14 Statistics……………………………………………………………………36 3. RESULTS………………………………………………………………………..37 3.1 CD86 stimulation on a CD40L/IL-4-activated B cell increases the phosphorylation and activation of IKKαβ………………………...37 3.2 CD86 stimulation on a CD40L/IL-4-activated B cell increases the phosphorylation and activation of Akt and PDK1………………...42 3.3 CD86 stimulation on a CD40L/IL-4-activated B cell ix increases the activity of PI3K……………………………………………………45 3.4 CD86 stimulation on a CD40L/IL-4-activated B cell increases the phosphorylation of PKCαβ and PLCγ2….………………………..48 3.5 CD86 induces an increase in NF-κB- and 3’-IgH enhancer- mediated gene activity…………………………………………………………...52 3.6 CD86-deficient B cells produce less IgG1 and Oct-2 in vivo…………………………………………………………...57 3.7 CD86 signaling in a B cell is CD19-dependent……………………………..63 3.8 CD86 stimulation on a CD40L/IL-4-activated B cell increases the phosphorylation and activation of CD19…………………………..70 3.9 CD86 stimulation
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